Pyridinone mk2 inhibitors and uses thereof

ABSTRACT

Described herein are MK2 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, neoplastic disorders, and cardiovascular or cerebrovascular disorders.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application Ser.No. 63/220,322 filed Jul. 9, 2021 and U.S. Provisional Application Ser.No. 63/340,079 filed May 10, 2022, which are hereby incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION

Mitogen-activated protein kinases (MAPK) are a conserved family ofenzymes that relay and propagate external stimuli, using phosphorylationcascades to generate a coordinated cellular response to the environment.The MAPK are proline-directed serine/threonine-specific protein kinasesthat regulate cellular activities, such as gene expression, mitosis,differentiation, and cell survival/apoptosis. To date, four distinctclasses of mammalian MAPK have been identified: the extracellularsignaling kinases (ERK1 and 2), the c-jun N-terminal kinase-1 (JNK1-3),the p38 MAPK (p38α, β, γ, and δ), and ERK5. The MAPK are activated bythe dual phosphorylation of Thr and Tyr residues within a TXY activationmotif by coordinated dual-specificity MAPKK, where X is Glu, Pro, andGly in ERK, JNK, and p38 MAPK, respectively. MAPK are 60-70% identicalto each other, yet differ in their activation loop sequences and sizes.The activation loop is adjacent to the enzyme-active site, and itsphosphorylation allows the enzyme to reposition active-site residuesinto the optimal orientation for substrate binding and catalysis.Downstream substrates of MAPK include mitogen-activatedprotein-kinase-activated protein (MAPKAP) kinases and transcriptionfactors, the phosphorylation of which, either directly or indirectly,regulates gene expression at several points, including transcription,nuclear export, and mRNA stability and translation. The cellularconsequences of MAPK activation include inflammation, apoptosis,differentiation, and proliferation.

Distinct genes encode four p38 MAPK in humans: ρ38α, β, γ, and δ.Significant amino acid sequence homology is observed among the 4isoforms, with 60-75 overall sequence identity and >90% identity withinthe kinase domains. Tissue-selective expression is observed, with ρ38γfound predominantly in skeletal muscle, ρ38δ in the testes, pancreas,and small intestine. In contrast, p38a and β are more ubiquitouslyexpressed.

p38 MAPK is the major isoform involved in the immune and inflammatoryresponse. As such its function is critical for the production andactivity of multiple proinflammatory cytokines, including TNFa, IL-1,IL-6, and IL-8, in cells such as macrophages, monocytes, synovial cells,and endothelial cells. p38 MAPK is also responsible for the induction ofkey inflammatory enzymes such as COX2 and iNOS, the major sources ofeicosanoids and nitric oxide at sites of inflammation, respectively.Additionally, the p38 MAPK pathway regulates the expression of matrixmetalloproteinases (MMP), including MMP2, MMP9, and MMP13.

The use of selective and potent inhibitors has facilitated the discoveryof several families of p38 MAPK substrates, including transcriptionfactors, MAPKAP kinases, and other enzymes. p38 MAPK can directlyphosphorylate several transcription factors, such as myocyte—specificenhancer binding factor 2C (MEF2C), CHOP, peroxisomeproliferator-activated receptor (PPAR) a, PPAR γ co-activator 1 and p53.These transcription factors are involved in cellular functions such asapoptosis, gluconeogenesis, and synthesis of enzymes involved in fattyacid oxidation. p38 MAPK is also involved in the direct or indirectphosphorylation of enzyme substrates, such as cytosolic phospholipaseA2, and the Cdc25 phosphatases, which are involved in the activation ofcyclin-dependent protein kinase activity and cell-cycle regulation.Therefore in addition to its role in the inflammatory response, p38 MAPKhas other functions associated with normal and abnormal cell growth andsurvival as well as cellular function and homeostasis. The MAPKAPkinases (MK2, MK-3, and PRAK) are selectively phosphorylated by p38MAPK, while the phosphorylation of MSK1/2, MNK1/2, and RSKb is catalyzedby both p38 MAPK and ERK.

MK-2, MK-3, and PRAK, once phosphorylated and activated by p38 MAPK,share similar substrate specificities. All of these kinases canphosphorylate the small heat-shock protein Hsp27. Studies have shownthat the PRAK- and MK3-deficient mice do not display any resistance toendotoxic shock or a decrease in lipopolysaccharide-(LPS)-inducedcytokine production. In contrast, MK-2-deficient mice show a resistanceto endotoxic shock and an impaired inflammatory response, as well as asignificantly decreased production of cytokines such as TNFa, IFNy andIL-6. Thus, the p38/MK2 axis is important for mediating pro-inflammatoryresponses.

The p38:MK2 complex is very stable with a Kd of 6 nM. The bindingaffinity of p38 for MK2 is driven by the C-terminal domain of MK2containing several positively charged amino acid residues.Crystallographic studies of the p38:MK2 complex demonstrated that theC-terminal region of MK2 wraps around p38a and binds to the negativelycharged ED binding site. The tight binding of p38 to MK2 may give riseto conformational changes providing additional binding pockets forinhibitors that would specifically be dependent upon the p38:MK2interaction. Taken together, these two studies suggests that selectivep38/MK2 axis blockade is achievable with small molecule inhibitors. Incomparison to traditional p38 MAPK inhibitors these p38/MK2 inhibitorsshould retain or enhance potency and exhibit improved safety features inanimal models of disease or in human clinical settings.

The p38/MK2 role in the regulation of inflammatory cytokines (TNFa,IL-Iβ, IL-6) and enzymes responsible for inflammation (COX-2, iNOS, andMMPs) makes it an attractive drug target. Several classical p38 MAPKinhibitors have progressed to testing in clinical trials. Some of thesecandidates have failed, for safety or other reasons, but several havereported clinical data in diseases such as rheumatoid arthritis, pain,Crohn's disease, acute coronary syndrome, multiple myeloma, and chronicobstructive pulmonary disease. In addition to these diseases severalIL-Iβ mediated diseases could be impacted by a p38 inhibitor based uponthe key role for the p38 MAPK pathway in the biosynthesis and activityof this cytokine. These diseases include the family of cryopyrinassociated periodic disorders (CAPS), chronic gout, diabetes, Still'sdisease, Familial Mediterranean Fever, among others. There is a need fornew safe and effective p38/MK2 inhibitors.

SUMMARY OF THE INVENTION

Disclosed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or rotamer thereof:

-   wherein:-   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   each R¹⁰ is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    aryl, and heteroaryl is optionally and independently substituted    with one or more R^(10a);-   or two R¹⁰ on the same atom are taken together to form an oxo; each    R¹⁰a is independently deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),    —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),    —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   or two R^(10a) on the same atom are taken together to form an oxo; n    is 1-4;-   R¹ and R² are independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl;-   or R¹ and R² are taken together to form an oxo;-   or R¹ and R² are taken together to form a cycloalkyl or    heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is    optionally substituted with deuterium, halogen, —CN, —OH, —OCH₃,    —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   X is —C(R³)₂—, —NR⁴—, —O—, or —S—;-   each R³ are independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl;-   or two R³ are taken together to form an oxo;-   R⁴ is hydrogen, —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, or heterocycloalkyl;-   R⁵ is hydrogen, deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),    —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, or heterocycloalkyl;-   R⁶ is hydrogen, deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),    —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, or heterocycloalkyl;-   R⁷ is hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or    C₁-C₆deuteroalkyl;-   Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   each R¹¹ is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    aryl, and heteroayl is optionally and independently substituted with    one or more R^(11a);-   or two R¹¹ on the same atom are taken together to form an oxo;-   each R^(11a) is independently deuterium, halogen, —CN, —NO₂, —OH,    —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   or two R^(11a) on the same atom are taken together to form an oxo;-   m is 1-4;-   Ring C is N-linked pyridinone, N-linked pyrimidinone, N-linked    pyrazinone, N-linked pyridazinone, N-linked dihydroimidazolone,    N-linked tetrahydropyrimidinone, N-linked piperazinone, or N-linked    tetrahydropyridazinone;-   each R¹² is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —S(═O)(═NR^(b))R^(a), —SiR^(c)R^(d)OR^(b), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(ayl), or    C₁-C₆alkylene(heteroayl); wherein the alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and    independently substituted with one or more R^(12a);-   each R^(12a) is independently deuterium, halogen, —CN, —NO₂, —OH,    —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a),    —C(═O)C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    —C(═O)C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl;-   or two R^(12a) on the same atom are taken together to form an oxo;-   p is 1-4;-   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), or    C₁-C₆alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one or more oxo, deuterium, halogen,    —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,    —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH,    —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   each R^(b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), or    C₁-C₆alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one or more oxo, deuterium, halogen,    —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,    —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH,    —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; and-   each R^(c) and R^(d) are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),    C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one or more    oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃,    —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂,    —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   or R^(c) and R^(d) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃,    —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃,    —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   or R^(b) and R^(c) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃,    —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃,    —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   or R^(a) and R^(b) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃,    —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃,    —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   or two R^(b) are taken together with the atom to which they are    attached to form a heterocycloalkyl optionally substituted with one    or more oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃,    —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃,    —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl.

Also disclosed herein is a pharmaceutical composition comprising acompound disclosed herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or rotamer thereof, and a pharmaceuticallyacceptable carrier.

Also disclosed herein is a method for treating a condition comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or rotamer thereof, wherein the conditionis selected from the group consisting of an autoimmune disorder, achronic inflammatory disorder, an acute inflammatory disorder, anauto-inflammatory disorder, a fibrotic disorder, a metabolic disorder, aneoplastic disorder, and a cardiovascular or a cerebrovascular disorder.

Also disclosed herein is a method of treating a p38 MAP kinase-mediateddisease in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt, solvate, stereoisomer, orrotamer thereof.

Also disclosed herein is a method of treating a MK2-mediated disease ina subject in need thereof comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “some embodiments” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with the embodiment is includedin at least one embodiment. Thus, the appearances of the phrases “in oneembodiment” or “in an embodiment” in various places throughout thisspecification are not necessarily all referring to the same embodiment.Furthermore, the particular features, structures, or characteristics maybe combined in any suitable manner in one or more embodiments. Also, asused in this specification and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the content clearlydictates otherwise. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“oxo” refers to ═O.

“Carboxyl” refers to —COOH.

“Alkyl” refers to a straight-chain, or branched-chain saturatedhydrocarbon monoradical having from one to about ten carbon atoms, morepreferably one to six carbon atoms. Examples include, but are notlimited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, suchas heptyl, octyl and the like. Whenever it appears herein, a numericalrange such as “C₁-C₆ alkyl” or “C₁-6alkyl”, means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, 5 carbon atoms or 6 carbon atoms, although the present definitionalso covers the occurrence of the term “alkyl” where no numerical rangeis designated. In some embodiments, the alkyl is a C₁₋₁₀alkyl. In someembodiments, the alkyl is a C₁₋₆alkyl. In some embodiments, the alkyl isa C₁₋₅alkyl. In some embodiments, the alkyl is a C₁₋₄alkyl. In someembodiments, the alkyl is a C₁₋₃alkyl. Unless stated otherwisespecifically in the specification, an alkyl group may be optionallysubstituted, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, thealkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe,—OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkyl is optionallysubstituted with halogen, —CN, —OH, or —OMe. In some embodiments, thealkyl is optionally substituted with halogen.

“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbonmonoradical having one or more carbon-carbon double-bonds and havingfrom two to about ten carbon atoms, more preferably two to about sixcarbon atoms. The group may be in either the cis or trans conformationabout the double bond(s), and should be understood to include bothisomers. Examples include, but are not limited to ethenyl (—CH═CH₂),1-propenyl (—CH₂CH═CH₂), isopropenyl [—C(CH₃)—CH₂], butenyl,1,3-butadienyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkenyl” or “C₂₋₆alkenyl”, means that the alkenylgroup may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5carbon atoms or 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkenyl” where no numerical range isdesignated. Unless stated otherwise specifically in the specification,an alkenyl group may be optionally substituted, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike. In some embodiments, the alkenyl is optionally substituted withoxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the alkenyl is optionally substituted with halogen, —CN,—OH, or —OMe. In some embodiments, the alkenyl is optionally substitutedwith halogen.

“Alkynyl” refers to a straight-chain or branched-chain hydrocarbonmonoradical having one or more carbon-carbon triple-bonds and havingfrom two to about ten carbon atoms, more preferably from two to aboutsix carbon atoms. Examples include, but are not limited to ethynyl,2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appearsherein, a numerical range such as “C₂-C₆ alkynyl” or “C₂₋₆alkynyl”,means that the alkynyl group may consist of 2 carbon atoms, 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although thepresent definition also covers the occurrence of the term “alkynyl”where no numerical range is designated. Unless stated otherwisespecifically in the specification, an alkynyl group may be optionallysubstituted, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, thealkynyl is optionally substituted with oxo, halogen, —CN, —COOH, COOMe,—OH, —OMe, —NH₂, or —NO₂. In some embodiments, the alkynyl is optionallysubstituted with halogen, —CN, —OH, or —OMe. In some embodiments, thealkynyl is optionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain.Unless stated otherwise specifically in the specification, an alkylenegroup may be optionally substituted, for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike. In some embodiments, the alkylene is optionally substituted withoxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the alkylene is optionally substituted with halogen, —CN,—OH, or —OMe. In some embodiments, the alkylene is optionallysubstituted with halogen.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted, forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl,alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, the alkoxy is optionallysubstituted with halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH₂, or —NO₂.In some embodiments, the alkoxy is optionally substituted with halogen,—CN, —OH, or —OMe. In some embodiments, the alkoxy is optionallysubstituted with halogen.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising 6 to 30 carbon atoms and at least one aromatic ring. The arylradical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ringsystem, which may include fused (when fused with a cycloalkyl orheterocycloalkyl ring, the aryl is bonded through an aromatic ring atom)or bridged ring systems. In some embodiments, the aryl is a 6- to10-membered aryl. In some embodiments, the aryl is a 6-membered aryl(phenyl). Aryl radicals include, but are not limited to, aryl radicalsderived from the hydrocarbon ring systems of anthrylene, naphthylene,phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unlessstated otherwise specifically in the specification, an aryl may beoptionally substituted, for example, with halogen, amino, nitrile,nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl,carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and thelike. In some embodiments, the aryl is optionally substituted withhalogen, methyl, ethyl, —CN, —COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or—NO₂. In some embodiments, the aryl is optionally substituted withhalogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments,the aryl is optionally substituted with halogen.

“Cycloalkyl” refers to a partially or fully saturated, monocyclic, orpolycyclic carbocyclic ring, which may include fused (when fused with anaryl or a heteroaryl ring, the cycloalkyl is bonded through anon-aromatic ring atom) or bridged ring systems. In some embodiments,the cycloalkyl is fully saturated. Representative cycloalkyls include,but are not limited to, cycloalkyls having from three to fifteen carbonatoms (C₃-C₁₅ cycloalkyl or C₃-C₁₅ cycloalkenyl), from three to tencarbon atoms (C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkenyl), from three toeight carbon atoms (C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl), from threeto six carbon atoms (C₃-C₆ cycloalkyl or C₃-C₆ cycloalkenyl), from threeto five carbon atoms (C₃-C₅ cycloalkyl or C₃-C₅ cycloalkenyl), or threeto four carbon atoms (C₃-C₄ cycloalkyl or C₃-C₄ cycloalkenyl). In someembodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In someembodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl,norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane,cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane,and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkylsinclude, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Unless stated otherwise specifically in the specification,a cycloalkyl is optionally substituted, for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, a cycloalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH,COOMe, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, a cycloalkylis optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃,—OH, or —OMe. In some embodiments, the cycloalkyl is optionallysubstituted with halogen.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In someembodiments, halogen is fluoro or chloro. In some embodiments, halogenis fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more hydroxyls. In some embodiments, the alkyl issubstituted with one hydroxyl. In some embodiments, the alkyl issubstituted with one, two, or three hydroxyls. Hydroxyalkyl include, forexample, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, orhydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

“Aminoalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more amines. In some embodiments, the alkyl issubstituted with one amine. In some embodiments, the alkyl issubstituted with one, two, or three amines. Aminoalkyl include, forexample, aminomethyl, aminoethyl, aminopropyl, aminobutyl, oraminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

“Deuteroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more deuteriums. In some embodiments, the alkyl issubstituted with one deuterium. In some embodiments, the alkyl issubstituted with one, two, or three deuteriums. In some embodiments, thealkyl is substituted with one, two, three, four, five, or sixdeuteriums. Deuteroalkyl include, for example, CD₃, CH₂D, CHD₂, CH₂CD₃,CD₂CD₃, CHDCD₃, CH₂CH₂D, or CH₂CHD₂. In some embodiments, thedeuteroalkyl is CD₃.

“Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, phosphorus, orcombinations thereof. A heteroalkyl is attached to the rest of themolecule at a carbon atom of the heteroalkyl. In one aspect, aheteroalkyl is a C₁-C₆ heteroalkyl wherein the heteroalkyl is comprisedof 1 to 6 carbon atoms and one or more atoms other than carbon, e.g.,oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, phosphorus, orcombinations thereof wherein the heteroalkyl is attached to the rest ofthe molecule at a carbon atom of the heteroalkyl. Examples of suchheteroalkyl are, for example, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃,—CH(CH₃)OCH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂CH₂NHCH₃, or —CH₂CH₂N(CH₃)₂.Unless stated otherwise specifically in the specification, a heteroalkylis optionally substituted for example, with oxo, halogen, amino,nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy,aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, a heteroalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments,a heteroalkyl is optionally substituted with oxo, halogen, methyl,ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, the heteroalkyl isoptionally substituted with halogen.

“Heterocycloalkyl” refers to a 3- to 24-membered partially or fullysaturated ring radical comprising 2 to 23 carbon atoms and from one to 8heteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur. In some embodiments, the heterocycloalkyl isfully saturated. In some embodiments, the heterocycloalkyl comprises oneto three heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprisesone to three heteroatoms selected from the group consisting of nitrogenand oxygen. In some embodiments, the heterocycloalkyl comprises one tothree nitrogens. In some embodiments, the heterocycloalkyl comprises oneor two nitrogens. In some embodiments, the heterocycloalkyl comprisesone nitrogen. In some embodiments, the heterocycloalkyl comprises onenitrogen and one oxygen. Unless stated otherwise specifically in thespecification, the heterocycloalkyl radical may be a monocyclic,bicyclic, tricyclic, or tetracyclic ring system, which may include fused(when fused with an aryl or a heteroaryl ring, the heterocycloalkyl isbonded through a non-aromatic ring atom) or bridged ring systems; andthe nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radicalmay be optionally oxidized; the nitrogen atom may be optionallyquaternized. Representative heterocycloalkyls include, but are notlimited to, heterocycloalkyls having from two to fifteen carbon atoms(C₂-C₁₅ heterocycloalkyl or C₂-C₁₅ heterocycloalkenyl), from two to tencarbon atoms (C₂-C₁₀ heterocycloalkyl or C₂-C₁₀ heterocycloalkenyl),from two to eight carbon atoms (C₂-C₈ heterocycloalkyl or C₂-C₈heterocycloalkenyl), from two to seven carbon atoms (C₂-C₇heterocycloalkyl or C₂-C₇ heterocycloalkenyl), from two to six carbonatoms (C₂-C₆ heterocycloalkyl or C₂-C₇ heterocycloalkenyl), from two tofive carbon atoms (C₂-C₅ heterocycloalkyl or C₂-C₅ heterocycloalkenyl),or two to four carbon atoms (C₂-C₄ heterocycloalkyl or C₂-C₄heterocycloalkenyl). Examples of such heterocycloalkyl radicals include,but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl,3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ringforms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides, and the oligosaccharides. Unlessotherwise noted, heterocycloalkyls have from 2 to 10 carbons in thering. It is understood that when referring to the number of carbon atomsin a heterocycloalkyl, the number of carbon atoms in theheterocycloalkyl is not the same as the total number of atoms (includingthe heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atomsof the heterocycloalkyl ring). In some embodiments, the heterocycloalkylis a 3- to 8-membered heterocycloalkyl. In some embodiments, theheterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In someembodiments, the heterocycloalkyl is a 3- to 6-memberedheterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to6-membered heterocycloalkyl. In some embodiments, the heterocycloalkylis a 5- to 6-membered heterocycloalkyl. In some embodiments, theheterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In someembodiments, the heterocycloalkyl is a 3- to 7-memberedheterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkylis a 4- to 6-membered heterocycloalkenyl. In some embodiments, theheterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless statedotherwise specifically in the specification, a heterocycloalkyl may beoptionally substituted as described below, for example, with oxo,halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, theheterocycloalkyl is optionally substituted with oxo, halogen, methyl,ethyl, —CN, —COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, the heterocycloalkyl is optionally substituted withhalogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments,the heterocycloalkyl is optionally substituted with halogen.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising one to thirteen carbon atoms, one to six heteroatoms selectedfrom the group consisting of nitrogen, oxygen, phosphorous, and sulfur,and at least one aromatic ring. In some embodiments, the heteroarylcomprises one to three heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur. In some embodiments, the heteroarylcomprises one to three heteroatoms selected from the group consisting ofnitrogen and oxygen. In some embodiments, the heteroaryl comprises oneto three nitrogens. In some embodiments, the heteroaryl comprises one ortwo nitrogens. In some embodiments, the heteroaryl comprises onenitrogen. The heteroaryl radical may be a monocyclic, bicyclic,tricyclic, or tetracyclic ring system, which may include fused (whenfused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl isbonded through an aromatic ring atom) or bridged ring systems; and thenitrogen, carbon, or sulfur atoms in the heteroaryl radical may beoptionally oxidized; the nitrogen atom may be optionally quaternized. Insome embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. Insome embodiments, the heteroaryl is a 5- to 6-membered heteroayl. Insome embodiments, the heteroaryl is a 6-membered heteroaryl. In someembodiments, the heteroaryl is a 5-membered heteroaryl. Examplesinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl,quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl,thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, andthiophenyl (i.e., thienyl). Unless stated otherwise specifically in thespecification, a heteroaryl may be optionally substituted, for example,with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl,heterocycloalkyl, heteroayl, and the like. In some embodiments, theheteroaryl is optionally substituted with halogen, methyl, ethyl, —CN,—COOH, COOMe, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, theheteroaryl is optionally substituted with halogen, methyl, ethyl, —CN,—CF₃, —OH, or —OMe. In some embodiments, the heteroayl is optionallysubstituted with halogen.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc.). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons.

The term “one or more” when referring to an optional substituent meansthat the subject group is optionally substituted with one, two, three,four, or more substituents. In some embodiments, the subject group isoptionally substituted with one, two, three, or four substituents. Insome embodiments, the subject group is optionally substituted with one,two, or three substituents. In some embodiments, the subject group isoptionally substituted with one or two substituents. In someembodiments, the subject group is optionally substituted with onesubstituent. In some embodiments, the subject group is optionallysubstituted with two substituents.

An “effective amount” or “therapeutically effective amount” refers to anamount of a compound administered to a mammalian subject, either as asingle dose or as part of a series of doses, which is effective toproduce a desired therapeutic effect.

“Treatment” of an individual (e.g. a mammal, such as a human) or a cellis any type of intervention used in an attempt to alter the naturalcourse of the individual or cell. In some embodiments, treatmentincludes administration of a pharmaceutical composition, subsequent tothe initiation of a pathologic event or contact with an etiologic agentand includes stabilization of the condition (e.g., condition does notworsen) or alleviation of the condition.

“Synergy” or “synergize” refers to an effect of a combination that isgreater than additive of the effects of each component alone at the samedoses.

As used herein, a “disease or disorder associated with MK2” or,alternatively, “an MK2-mediated disease or disorder” means any diseaseor other deleterious condition in which MK2, or a mutant thereof, isknown or suspected to play a role.

As used herein, a “disease or disorder associated with p3S MAP kinase”or, alternatively, “a p38 MAP kinase-mediated disease or disorder” meansany disease or other deleterious condition in which p38 MAP kinase, or amutant thereof, is known or suspected to play a role.

Compounds

Described herein are compounds of Formula (I)-(Ia)-(Ij), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof useful in the treatment of autoimmune disorders, chronicinflammatory disorders, acute inflammatory disorders, auto-inflammatorydisorders, fibrotic disorders, metabolic disorders, neoplasticdisorders, or cardiovascular or cerebrovascular disorders.

Disclosed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or rotamer thereof:

-   wherein:-   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   each R¹⁰ is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    aryl, and heteroayl is optionally and independently substituted with    one or more R^(10a);-   or two R¹⁰ on the same atom are taken together to form an oxo; each    R^(10a) is independently deuterium, halogen, —CN, —NO₂, —OH,    —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   or two R^(10a) on the same atom are taken together to form an oxo;-   n is 1-4;-   R¹ and R² are independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl;-   or R¹ and R² are taken together to form an oxo;-   or R¹ and R² are taken together to form a cycloalkyl or    heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is    optionally substituted with deuterium, halogen, —CN, —OH, —OCH₃,    —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   X is —C(R³)₂—, —NR⁴—, —O—, or —S—;-   each R³ are independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl; or two R³ are taken    together to form an oxo;-   R⁴ is hydrogen, —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, or heterocycloalkyl;-   R⁵ is hydrogen, deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),    —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, or heterocycloalkyl;-   R⁶ is hydrogen, deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),    —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, or heterocycloalkyl;-   R⁷ is hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or    C₁-C₆deuteroalkyl;-   Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   each R¹¹ is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,    aryl, and heteroaryl is optionally and independently substituted    with one or more R^(11a);-   or two R¹ on the same atom are taken together to form an oxo;-   each R^(11a) is independently deuterium, halogen, —CN, —NO₂, —OH,    —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b),    —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;-   or two R^(11a) on the same atom are taken together to form an oxo;-   m is 1-4;-   Ring C is N-linked pyridinone, N-linked pyrimidinone, N-linked    pyrazinone, N-linked pyridazinone, N-linked dihydroimidazolone,    N-linked tetrahydropyrimidinone, N-linked piperazinone, or N-linked    tetrahydropyridazinone;-   each R¹² is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OH, —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —S(═O)(═NR^(b))R^(a), —SiR^(c)R^(d)OR^(b), —NR^(c)R^(d),    —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),    —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(ayl), or    C₁-C₆alkylene(heteroaryl); wherein the alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and    independently substituted with one or more R^(12a);-   each R^(12a) is independently deuterium, halogen, —CN, —NO₂, —OH,    —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH,    —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),    —NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),    —NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a),    —C(═O)C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),    —C(═O)C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl;-   or two R^(12a) on the same atom are taken together to form an oxo;-   p is 1-4;-   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), or    C₁-C₆alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one or more oxo, deuterium, halogen,    —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,    —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH,    —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   each R^(b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,    C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),    C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), or    C₁-C₆alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently    optionally substituted with one or more oxo, deuterium, halogen,    —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,    —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH,    —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,    C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; and-   each R^(c) and R^(d) are independently hydrogen, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    cycloalkyl, heterocycloalkyl, aryl, heteroaryl,    C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),    C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and    heteroaryl is independently optionally substituted with one or more    oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃,    —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂,    —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl,    C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or    C₁-C₆heteroalkyl;-   or R^(c) and R^(d) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃,    —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃,    —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   or R^(b) and R^(c) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃,    —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃,    —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   or R^(a) and R^(b) are taken together with the atom to which they    are attached to form a heterocycloalkyl optionally substituted with    one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃,    —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃,    —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl;-   or two R^(b) are taken together with the atom to which they are    attached to form a heterocycloalkyl optionally substituted with one    or more oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃,    —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃,    —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,    C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,    C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl.

Also disclosed herein is a compound of Formula (Ia), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (Ib), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (Ic), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (Id), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (Ie), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (If), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (Ig), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (Ih), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (Ii), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

Also disclosed herein is a compound of Formula (Ij), or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof:

In some embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or(Ii), Ring A is heteroaryl. In some embodiments of a compound of Formula(I), (Ia)-(Ie), (Ig), or (Ii), Ring A is a 6-membered heteroaryl. Insome embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or (Ii),Ring A is pyridyl. In some embodiments of a compound of Formula (I),(Ia)-(Ie), (Ig), or (Ii), Ring A is phenyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹⁰ isindependently hydrogen, deuterium, halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (I), (Ia)-(Ij), each R¹⁰ isindependently hydrogen, halogen, or C₁-C₆alkyl. In some embodiments of acompound of Formula (I), (Ia)-(Ij), each R¹⁰ is independently hydrogenor halogen.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹⁰ isindependently deuterium, halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (I), (Ia)-(Ij), each R¹⁰ is independently halogenor C₁-C₆alkyl. In some embodiments of a compound of Formula (I),(Ia)-(Ij), each R¹⁰ is independently halogen.

In some embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or(Ii), n is 1 or 2. In some embodiments of a compound of Formula (I),(Ia)-(Ie), (Ig), or (Ii), n is 2 or 3. In some embodiments of a compoundof Formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 1. In some embodiments ofa compound of Formula (I), (Ia)-(Ie), (Ig), or (Ii), n is 2. In someembodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or (Ii), n is3.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), R¹ and R²are independently hydrogen, deuterium, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (I), (Ia)-(Ij), R¹ and R² are independently hydrogen,deuterium, halogen, or C₁-C₆alkyl. In some embodiments of a compound ofFormula (I), (Ia)-(Ij), R¹ and R² are hydrogen. In some embodiments of acompound of Formula (I), (Ia)-(Ij), R¹ and R² are deuterium.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), X is —O—.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), R¹ ishydrogen, deuterium, halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkynyl, or cycloalkyl. In some embodiments of acompound of Formula (I), (Ia)-(Ij), R⁵ is hydrogen, deuterium, halogen,—CN, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I),(Ia)-(Ij), R⁵ is hydrogen. In some embodiments of a compound of Formula(I), (Ia)-(Ij), R⁶ is hydrogen, deuterium, halogen, —CN, or C₁-C₆alkyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), R⁶ ishydrogen, deuterium, halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkynyl, or cycloalkyl. In some embodiments of acompound of Formula (I), (Ia)-(Ij), R⁶ is hydrogen, deuterium, halogen,—CN, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I),(Ia)-(Ij), R⁶ is C₁-C₆alkyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), R⁷ ishydrogen, deuterium, halogen, or C₁-C₆haloalkyl. In some embodiments ofa compound of Formula (I), (Ia)-(Ij), R⁷ is hydrogen, deuterium, orhalogen. In some embodiments of a compound of Formula (I), (Ia)-(Ij), R⁷is halogen. In some embodiments of a compound of Formula (I), (Ia)-(Ij),R⁷ is chloro. In some embodiments of a compound of Formula (I),(Ia)-(Ij), R⁷ is bromo. In some embodiments of a compound of Formula(I), (Ia)-(Ij), R⁷ is —CHF₂.

In some embodiments of a compound of Formula (I), (Ia)-(Ie), (Ig), or(Ih), Ring B is a phenyl or a 6-membered heteroaryl. In some embodimentsof a compound of Formula (I), (Ia)-(Ie), (Ig), or (Ih), Ring B ispyridinyl. In some embodiments of a compound of Formula (I), (Ia)-(Ie),(Ig), or (Ih), Ring B is phenyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹¹ isindependently deuterium, halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkynyl, or cycloalkyl. In some embodiments of acompound of Formula (I), (Ia)-(Ij), each R¹¹ is independentlyC₁-C₆alkyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹¹ isindependently hydrogen, deuterium, halogen, —CN, —OH, —OR^(a),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkynyl, or cycloalkyl. In someembodiments of a compound of Formula (I), (Ia)-(Ij), each R¹¹ isindependently hydrogen or C₁-C₆alkyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is 1 or2. In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is1-4. In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is2-4. In some embodiments of a compound of Formula (I), (Ia)-(Ij), mis 1. In some embodiments of a compound of Formula (I), (Ia)-(Ij), m is2.

In some embodiments of a compound of Formula (I), (If), (Ig), Ring C isN-linked pyridinone, N-linked pyrimidinone, N-linked pyrazinone, orN-linked pyridazinone. In some embodiments of a compound of Formula (I),(If), (Ig), Ring C is N-linked pyridinone. In some embodiments of acompound of Formula (I), (If), (Ig), Ring C is N-linked pyrimidinone. Insome embodiments of a compound of Formula (I), (If), (Ig), Ring C isN-linked pyrazinone. In some embodiments of a compound of Formula (I),(If), (Ig), Ring C is N-linked pyridazinone.

In some embodiments of a compound of Formula (I), (If), (Ig), Ring C is

In some embodiments of a compound of Formula (I), (If), (Ig), Ring C is

In some embodiment of a compound of Formula (I), (If), (Ig), Ring C is

In some embodiments of a compound of Formula (I), (If), (Ig), Ring C is

In some embodiments of a compound of Formula (I), (If), (Ig), Ring C is

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently hydrogen, deuterium, halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein the alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally andindependently substituted with one or more R^(12a).

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently hydrogen, deuterium, halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylene(cycloalkyl), orC₁-C₆alkylene(heterocycloalkyl); wherein the alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is optionally and independentlysubstituted with one or more R^(12a).

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, cycloalkyl, heterocycloalkyl,C₁-C₆alkylene(cycloalkyl), or C₁-C₆alkylene(heterocycloalkyl); whereinthe alkyl, cycloalkyl, and heterocycloalkyl is optionally andindependently substituted with one or more R^(12a).

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently hydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl,cycloalkyl, and heterocycloalkyl is optionally and independentlysubstituted with one or more R^(12a).

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently hydrogen or C₁-C₆hydroxyalkyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently deuterium, halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein the alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally andindependently substituted with one or more R^(12a).

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently deuterium, halogen, —CN, —OH, —OR^(a), —NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), or C₁-C₆alkylene(heterocycloalkyl); whereinthe alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isoptionally and independently substituted with one or more R^(12a).

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, cycloalkyl, heterocycloalkyl,C₁-C₆alkylene(cycloalkyl), or C₁-C₆alkylene(heterocycloalkyl); whereinthe alkyl, cycloalkyl, and heterocycloalkyl is optionally andindependently substituted with one or more R^(12a).

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl,cycloalkyl, and heterocycloalkyl is optionally and independentlysubstituted with one or more R^(12a).

In some embodiments of a compound of Formula (I), (Ia)-(Ij), each R¹² isindependently C₁-C₆hydroxyalkyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), eachR^(12a) is independently deuterium, halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, cycloalkyl, or heterocycloalkyl.

In some embodiments of a compound of Formula (I), (Ia)-(Ij), eachR^(12a) is independently deuterium, halogen, —CN, —OH, —OR^(a),—NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl. In someembodiments of a compound of Formula (I), (Ia)-(Ij), each R^(12a) isindependently deuterium, halogen, —CN, —OH, —OR^(a), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (I), (If), or (Ig), p is 1or 2. In some embodiments of a compound of Formula (I), (If), or (Ig), pis 1-3. In some embodiments of a compound of Formula (I), (If), or (Ig),p is 1. In some embodiments of a compound of Formula (I), (If), or (Ig),p is 2.

In some embodiments of a compound disclosed herein, each R^(a) isindependently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂,—NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl. In some embodiments of a compound disclosed herein,each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃,—C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl. In someembodiments of a compound disclosed herein, each R^(a) is independentlyC₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl. In someembodiments of a compound disclosed herein, each R^(a) is independentlyC₁-C₆alkyl or C₁-C₆haloalkyl. In some embodiments of a compounddisclosed herein, each R^(a) is independently C₁-C₆alkyl.

In some embodiments of a compound disclosed herein, each R^(b) isindependently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂,—NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl. In some embodiments of a compound disclosed herein,each R^(b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃,—S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂,—C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl.In some embodiments of a compound disclosed herein, each R^(b) isindependently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, orheterocycloalkyl. In some embodiments of a compound disclosed herein,each R^(b) is independently hydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound disclosed herein, each R^(b) isindependently hydrogen or C₁-C₆alkyl.

In some embodiments of a compound disclosed herein, each R^(c) and R^(d)are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroayl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,—S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl. In some embodiments of a compounddisclosed herein, each R^(c) and R^(d) are independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH₃,—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂,—NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl. In some embodiments of a compound disclosed herein,each R^(c) and R^(d) are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments ofa compound disclosed herein, each R^(c) and R^(d) are independentlyhydrogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound disclosed herein, each R^(c) and R^(d) are independentlyhydrogen or C₁-C₆alkyl.

In some embodiments of a compound disclosed herein, R^(c) and R^(d) aretaken together with the atom to which they are attached to form aheterocycloalkyl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH,—C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl.

In some embodiments of a compound disclosed herein, each R¹⁰, R¹¹, R¹²,R^(a), R^(b), R^(c), R^(d), the heterocycloalkyl formed when R^(c) andR^(d) are taken together, the heterocycloalkyl formed when R^(a) andR^(b) are taken together, and the heterocycloalkyl formed when R^(b) andR^(c) are taken together is independently substituted with one, two,three, four, or five substituents as defined herein. In some embodimentsof a compound disclosed herein, each R¹⁰, R¹¹, R¹², R^(a), R^(b), R^(c),R^(d), the heterocycloalkyl formed when R^(c) and R^(d)are takentogether, the heterocycloalkyl formed when R^(a) and R^(b) are takentogether, and the heterocycloalkyl formed when R^(b) and R^(c) are takentogether is independently substituted with one, two, three, or foursubstituents as defined herein. In some embodiments of a compounddisclosed herein, each R¹⁰, R¹¹, R¹², R^(a), R^(b), R^(c), R^(d), theheterocycloalkyl formed when R^(c) and R^(d) are taken together, theheterocycloalkyl formed when R^(a) and R^(b) are taken together, and theheterocycloalkyl formed when R^(b) and R^(c) are taken together isindependently substituted with one, two, or three substituents asdefined herein. In some embodiments of a compound disclosed herein, eachR¹⁰, R¹¹, R¹², R^(a), R^(b), R^(c), R^(d), the heterocycloalkyl formedwhen R^(c) and R^(d)are taken together, the heterocycloalkyl formed whenR^(a) and R^(b) are taken together, and the heterocycloalkyl formed whenR^(b) and R^(c) are taken together is independently substituted with oneor two substituents as defined herein. In some embodiments of a compounddisclosed herein, each R¹⁰, R¹, R¹², R^(a), R^(b), R^(c), R^(d), theheterocycloalkyl formed when R^(c) and R^(d) are taken together, theheterocycloalkyl formed when R^(a) and R^(b) are taken together, and theheterocycloalkyl formed when R^(b) and R^(c) are taken together isindependently substituted with one substituent as defined herein.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or rotamer thereof, is selectedfrom:

Ex. Structure  1A

 1B

 2A

 2B

 3A

 3B

 4A

 4B

 5A

 5B

 6

 7A

 7B

 8A

 8B

 9A

 9B

10A

10B

11A

11B

12A

12B

13A

13B

14A

14B

14C

14D

15A

15B

16A

16B

17A

17B

18A

18B

19A

19B

20A

20B

21A

21B

22A

22B

23A

23B

24A

24B

25A

25B

26A

26B

27A

27B

28A

28B

Note: all rotamers found in table 1 were arbitrarily assigned.

In some embodiments the compound of Formula (I) is selected from: OH

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.

Further Forms of Compounds Disclosed Herein Isomers Stereoisomers

In some embodiments, the compounds described herein exist as geometricisomers. In some embodiments, the compounds described herein possess oneor more double bonds. The compounds presented herein include all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof. In some situations, the compoundsdescribed herein possess one or more chiral centers and each centerexists in the R configuration, or S configuration. The compoundsdescribed herein include all diastereomeric, enantiomeric, and epimericforms as well as the corresponding mixtures thereof. In additionalembodiments of the compounds and methods provided herein, mixtures ofenantiomers and/or diastereoisomers, resulting from a single preparativestep, combination, or interconversion are useful for the applicationsdescribed herein. In some embodiments, the compounds described hereinare prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred. In some embodiments, thediastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and are separated bytaking advantage of these dissimilarities. In some embodiments, thediastereomers are separated by chiral chromatography, or preferably, byseparation/resolution techniques based upon differences in solubility.In some embodiments, the optically pure enantiomer is then recovered,along with the resolving agent, by any practical means that would notresult in racemization.

In some embodiments, the compounds described herein exist as rotamerscaused by the slow rotation of the N—C bond between the centralpyridinone ring and Ring B.

In some embodiments,

exists as

For example OH exists as OH or OH

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds disclosed herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and thepharmaceutically acceptable salts, solvates, stereoisomers, or rotamersthereof which contain the aforementioned isotopes and/or other isotopesof other atoms are within the scope of this invention. Certainisotopically-labeled compounds, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i.e., ³H and carbon-14,i.e., 14C, isotopes are particularly preferred for their ease ofpreparation and detectability. Further, substitution with heavy isotopessuch as deuterium, i.e., ²H, produces certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds disclosed herein, or a solvate, stereoisomer, or rotamersthereof, or by separately reacting a purified compound in its free formwith a suitable acid or base, and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid or inorganic base, such salts including, acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylateundeconate and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid and muconic acid. In some embodiments, other acids,such as oxalic, while not in themselves pharmaceutically acceptable, areemployed in the preparation of salts useful as intermediates inobtaining the compounds disclosed herein, solvate, stereoisomer, orrotamer thereof and their pharmaceutically acceptable acid additionsalts.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary, tertiary, or quaternary amine. Representative saltsinclude the alkali or alkaline earth salts, like lithium, sodium,potassium, calcium, and magnesium, and aluminum salts and the like.Illustrative examples of bases include sodium hydroxide, potassiumhydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄ alkyl)₄, and thelike.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. In some embodiments,water or oil-soluble or dispersible products are obtained by suchquaternization.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of the compounds described herein can beconveniently prepared or formed during the processes described herein.By way of example only, hydrates of the compounds described herein canbe conveniently prepared from an aqueous/organic solvent mixture, usingorganic solvents including, but not limited to, dioxane, tetrahydrofuranor methanol. In addition, the compounds provided herein can exist inunsolvated as well as solvated forms. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thecompounds and methods provided herein.

Tautomers

In some situations, compounds exist as tautomers. The compoundsdescribed herein include all possible tautomers within the formulasdescribed herein. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH.

Method of Treatment

Described herein are compounds and compositions generally useful for theinhibition of kinase activity of one or more enzymes. Examples ofkinases that are inhibited by the compounds and compositions describedherein and against which the methods described herein are useful includep38 MAP kinase, MK2, or a mutant thereof.

MAP kinase-activated protein kinase 2 (“MK2”) is an enzyme that inhumans is encoded by the MAPKAPK2 gene. This gene encodes a member ofthe Ser/Thr protein kinase family. This kinase is regulated throughdirect phosphorylation by p38 MAP kinase. In conjunction with p38 MAPkinase, this kinase is known to be involved in many cellular processesincluding stress and inflammatory responses, nuclear export, geneexpression regulation and cell proliferation. Heat shock protein HSP27was shown to be one of the substrates of this kinase in vivo. Twotranscript variants encoding two different isoforms have been found forthis gene.

MK2 is a multi-domain protein consisting of an N-terminal proline-richdomain, a catalytic domain, an autoinhibitory domain and at theC-terminus a nuclear export signal (NES) and nuclear localization signal(NLS). Two isoforms of human MK2 have been characterized. One isoformconsists of 400 amino acids and the other isoform 370 residues which isthought to be a splice variant missing the C-terminal NLS. MK2 islocated in the nucleus of the cell and upon binding and phosphorylationby p38, the MK2 NES becomes functional and both kinases areco-transported out of the nucleus to the cytoplasm. Interestingly,transport of the MK2/p38 complex does not require catalytically activeMK2, as the active site mutant, Asp207Ala, is still transported to thecytoplasm. Phosphorylation of human MK2 by p38 on residues T222, S272and T334 is thought to activate the enzyme by inducing a conformationalchange of the autoinhibitory domain thus exposing the active site forsubstrate binding. Mutations of two autoinhibitory domain residues W332Aand K326E in murine MK2 demonstrate an increase in basal activity and aC-terminal deletion of the autoinhibitory domain renders the enzymeconstitutively active, providing additional evidence to the role of thisdomain in inhibition of MK2 activity.

Diseases or disorders associated with MK2 that are treated by compoundsdisclosed herein include autoimmune disorders, chronic inflammatorydisorders, acute inflammatory disorders, auto-inflammatory disorders,fibrotic disorders, metabolic disorders, neoplastic disorders, andcardiovascular or cerebrovascular disorders.

In some embodiments, the MK2-mediated disease or disorder is anautoimmune disorder, chronic and/or acute inflammatory disorder, and/orauto-inflammatory disorder. Exemplary autoimmune and/or inflammatoryand/or auto-inflammatory disorders include: inflammatory bowel diseases(for example, ulcerative colitis or Crohn's disease), multiplesclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis,juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosingspondylitis, cryopyrin associated periodic syndromes, Muckle-Wellssyndrome, familial cold auto-inflammatory syndrome, neonatal-onsetmultisystem inflammatory disease, TNF receptor associated periodicsyndrome, acute and chronic pancreatitis, atherosclerosis, gout,ankylosing spondylitis, fibrotic disorders (for example, hepaticfibrosis or idiopathic pulmonary fibrosis), nephropathy, sarcoidosis,scleroderma, anaphylaxis, diabetes (for example, diabetes mellitus type1 or diabetes mellitus type 2), diabetic retinopathy, Still's disease,vasculitis, sarcoidosis, pulmonary inflammation, acute respiratorydistress syndrome, wet and dry age-related macular degeneration,autoimmune hemolytic syndromes, autoimmune and inflammatory hepatitis,autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis,autoimmune thrombocytopenia, silicone implant associated autoimmunedisease, Sjogren's syndrome, familial Mediterranean fever, systemiclupus erythematosus, vasculitis syndromes (for example, temporal,Takayasu's and giant cell arteritis, Behçet's disease or Wegener'sgranulomatosis), vitiligo, secondary hematologic manifestation ofautoimmune diseases (for example, anemias), drug-induced autoimmunity,Hashimoto's thyroiditis, hypophysitis, idiopathic thrombocytic purpura,metal-induced autoimmunity, myasthenia gravis, pemphigus, autoimmunedeafness (for example, Meniere's disease), Goodpasture's syndrome,Graves' disease, HW-related autoimmune syndromes, Guillain-Barredisease, Addison's disease, anti-phospholipid syndrome, asthma, atopicdermatitis, Celiac disease, Cushing's syndrome, dermatomyositis,idiopathic adrenal atrophy, idiopathic thrombocytopenia, Kawasakisyndrome, Lambert-Eaton Syndrome, pernicious anemia, pollinosis,polyarteritis nodosa, primary biliary cirrhosis, primary sclerosingcholangitis, Raynaud's, Reiter's Syndrome, relapsing polychondritis,Schmidt's syndrome, thyrotoxidosis, sepsis, septic shock, endotoxicshock, exotoxin-induced toxic shock, gram negative sepsis, toxic shocksyndrome, glomerulonephritis, peritonitis, interstitial cystitis,hyperoxia-induced inflammations, chronic obstructive pulmonay disease(COPD), vasculitis, graft vs. host reaction (for example, graft vs. hostdisease), allograft rejections (for example, acute allograft rejectionor chronic allograft rejection), early transplantation rejection (forexample, acute allograft rejection), reperfusion injury, pain (forexample, acute pain, chronic pain, neuropathic pain, or fibromyalgia),chronic infections, meningitis, encephalitis, myocarditis, gingivitis,post-surgical trauma, tissue injury, traumatic brain injury,enterocolitis, sinusitis, uveitis, ocular inflammation, optic neuritis,gastric ulcers, esophagitis, peritonitis, periodontitis,dermatomyositis, gastritis, myositis, polymyalgia, pneumonia andbronchitis.

In some embodiments, the MK2-mediated disease or disorder is a fibroticdisorder. Exemplary fibrotic disorders include systemicsclerosis/scleroderma, lupus nephritis, connective tissue disease, woundhealing, surgical scarring, spinal cord injury, CNS scarring, acute lunginjury, pulmonary fibrosis (for example, idiopathic pulmonary fibrosisor cystic fibrosis), chronic obstructive pulmonary disease, adultrespiratory distress syndrome, acute lung injury, drug-induced lunginjury, glomerulonephritis, chronic kidney disease (for example,diabetic nephropathy), hypertension-induced nephropathy, alimentarytrack or gastrointestinal fibrosis, renal fibrosis, hepatic or biliaryfibrosis, liver fibrosis (for example, nonalcoholic steatohepatitis,hepatitis C, or hepatocellular carcinoma), cirrhosis (for example,primary biliary cirrhosis or cirrhosis due to fatty liver disease (forexample, alcoholic and nonalcoholic steatosis)), radiation-inducedfibrosis (for example, head and neck, gastrointestinal or pulmonary),primary sclerosing cholangitis, restenosis, cardiac fibrosis (forexample, endomyocardial fibrosis or atrial fibrosis), ophthalmicscarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma,fibroadenomas, fibrosarcomas, transplant arteriopathy, keloid,mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, and nephrogenic systemic fibrosis.

In some embodiments, the MK2-mediated disease or disorder is a metabolicdisorder. Exemplary metabolic disorders include obesity,steroid-resistance, glucose intolerance, and metabolic syndrome.

In some embodiments, the MK2-mediated disease or disorder is aneoplastic disease or disorder. Exemplary neoplastic diseases ordisorders include cancers. In some embodiments, exemplary neoplasticdiseases or disorders include angiogenesis disorders, multiple myeloma,leukemias (for example, acute lymphocytic leukemia, acute and chronicmyelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblasticleukemia, or promyelocytic leukemia), lymphomas (for example, B-celllymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma,Burkitt's lymphoma, mast cell tumors, Hodgkin's disease or non-Hodgkin'sdisease), myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma,teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoctanthoma,thyroid follicular cancer, Kaposi's sarcoma, melanoma, teratoma,rhabdomyosarcoma, metastatic and bone disorders, as well as cancer ofthe bone, mouth/pharynx, esophagus, larynx, stomach, intestine, colon,rectum, lung (for example, non-small cell lung cancer or small cell lungcancer), liver, pancreas, nerve, brain (for example, glioma orglioblastoma multiforme), head and neck, throat, ovary, uterus,prostate, testis, bladder, kidney, breast, gall bladder, cervix,thyroid, prostate, and skin.

In some embodiments, the MK2-mediated disorder is a cardiovascular orcerebrovascular disorder. Exemplary cardiovascular disorders includeatherosclerosis, restenosis of an atherosclerotic coronary artery, acutecoronary syndrome, myocardial infarction, cardiac-allograft vasculopathyand stroke. Exemplary cerebrovascular diseases include central nervoussystem disorders with an inflammatory or apoptotic component,Alzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, spinal cord injury, neuronal ischemia,and peripheral neuropathy.

Dosing

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder, or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of or riskfactor for the disease being treated and is currently in remission, apharmaceutical composition comprising a compound described herein, or apharmaceutically acceptable salt thereof, in order to prevent a returnof the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage, or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent or daily treatment on along-term basis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg to about 1000 mgper day. In one embodiment, the desired dose is conveniently presentedin a single dose or in divided doses administered simultaneously or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In one embodiment, the daily dosages appropriate for the compounddescribed herein, or a pharmaceutically acceptable salt thereof, arefrom about 0.01 to about 50 mg/kg per body weight. In some embodiments,the daily dosage, or the amount of active in the dosage form are loweror higher than the ranges indicated herein, based on a number ofvariables in regard to an individual treatment regime. In variousembodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₁₀ and the ED₉₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe EDso with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound described herein, or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the subject every 12 hours; (v) the compound isadministered to the subject every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended, or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long-actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated with organspecific antibody. In such embodiments, the liposomes are targeted toand taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended-release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Compositions/Formulations

The compounds described herein are administered to a subject in needthereof, either alone or in combination with pharmaceutically acceptablecarriers, excipients, or diluents, in a pharmaceutical composition,according to standard pharmaceutical practice. In one embodiment, thecompounds of this invention may be administered to animals. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal, andtopical routes of administration.

In another aspect, provided herein are pharmaceutical compositionscomprising a compound described herein, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or rotamer thereof, and at least onepharmaceutically acceptable excipient. Pharmaceutical compositions areformulated in a conventional manner using one or more pharmaceuticallyacceptable excipients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

In some embodiments, the pharmaceutically acceptable excipient isselected from carriers, binders, filling agents, suspending agents,flavoring agents, sweetening agents, disintegrating agents, dispersingagents, surfactants, lubricants, colorants, diluents, solubilizers,moistening agents, plasticizers, stabilizers, penetration enhancers,wetting agents, anti-foaming agents, antioxidants, preservatives, andany combinations thereof.

The pharmaceutical compositions described herein are administered to asubject by appropriate administration routes, including, but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, liquids, gels, syrups,elixirs, slurries, suspensions, self-emulsifying dispersions, solidsolutions, liposomal dispersions, aerosols, solid oral dosage forms,powders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, powders,dragees, effervescent formulations, lyophilized formulations, delayedrelease formulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

Pharmaceutical compositions including compounds described herein, or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof are manufactured in a conventional manner, such as, by way ofexample only, by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orcompression processes.

Pharmaceutical compositions for oral use are obtained by mixing one ormore solid excipient with one or more of the compounds described herein,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include, for example,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents are added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate. In some embodiments, dyestuffs orpigments are added to the tablets or dragee coatings for identificationor to characterize different combinations of active compound doses.

Pharmaceutical compositions that are administered orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules contain the active ingredients in admixture with filler such aslactose, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive compounds are dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. In someembodiments, stabilizers are added.

Pharmaceutical compositions for parental use are formulated as infusionsor injections. In some embodiments, the pharmaceutical compositionsuitable for injection or infusion includes sterile aqueous solutions,or dispersions, or sterile powders comprising a compound describedherein, or a pharmaceutically acceptable salt, solvate, stereoisomer, orrotamer thereof. In some embodiments, the pharmaceutical compositioncomprises a liquid carrier. In some embodiments, the liquid carrier is asolvent or liquid dispersion medium comprising, for example, water,saline, ethanol, a polyol (for example, glycerol, propylene glycol,liquid polyethylene glycols, and the like), vegetable oils, nontoxicglyceryl esters, and any combinations thereof. In some embodiments, thepharmaceutical compositions further comprise a preservative to preventgrowth of microorganisms.

Combination

Disclosed herein are methods of treating an autoimmune disorder, achronic inflammatory disorder, an acute inflammatory disorder, anauto-inflammatory disorder, a fibrotic disorder, a metabolic disorder, aneoplastic disorder, or a cardiovascular or a cerebrovascular disorderusing a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or rotamer thereof, in combination with anadditional therapeutic agent.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of anti-inflammatory drugs, anti-atheroscleroticdrugs, immunosuppressive drugs, immunomodulatory drugs, cytostaticdrugs, anti-proliferative agents, angiogenesis inhibitors, kinaseinhibitors, cytokine blockers, and inhibitors of cell adhesionmolecules.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of NSAIDs, immunosuppressive drugs,immunomodulatory drugs, cytostatic drugs, antiproliferative agents,angiogenesis inhibitors, biological agents, steroids, vitamin D3analogs, retinoids, other kinase inhibitors, cytokine blockers,corticosteroids, and inhibitors of cell adhesion molecules. In someembodiments, the additional therapeutic agent is selected from the groupconsisting of torcetrapib, aspirin, niacin, HMG CoA reductase inhibitors(e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatinand simvastatin), colesevelam, cholestyramine, colestipol, gemfibrozil,probucol, and clofibrate.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of corticosteroids, nonsteroidal anti-inflammatorydrugs (NSAID) (e.g. ibuprofen, naproxen, acetaminophen, aspirin,Fenoprofen (Nalfon), Flurbiprofen (Ansaid), Ketoprofen, Oxaprozin(Daypro), Diclofenac sodium (Voltaren), Diclofenac potassium (Cataflam),Etodolac (Lodine), Indomethacin (Indocin), Ketorolac (Toradol), Sulindac(Clinoril), Tolmetin (Tolectin), Meclofenamate (Meclomen), Mefenamicacid (Ponstel), Nabumetone (Relafen), Piroxicam (Feldene), cox-2inhibitors (e.g., celecoxib (Celebrex))), immunosuppressants (e.g.,methotrexate (Rheumatrex), leflunomide (Arava), azathioprine (Imuran),cyclosporine (Neoral, Sandimmune), tacrolimus and cyclophosphamide(Cytoxan), CD20 blockers (Rituximab), Tumor Necrosis Factor (TNF)blockers (e.g., etanercept (Enbrel), infliximab (Remicade) andadalimumab (Humira)), Abatacept (CTLA4-Ig) and interleukin-1 receptorantagonists (e.g. Anakinra (Kineret), interleukin 6 inhibitors (e.g.,Actemra), interleukin 17 inhibitors (e.g., AIN457), Janus kinaseinhibitors (e.g., Tasocitinib), syk inhibitors (e.g. R788), andchloroquine and its derivatives.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of an EGFR kinase inhibitor, MEK inhibitor, VEGFRinhibitor, anti-VEGFR2 antibody, KDR antibody, AKT inhibitor, PDK-1inhibitor, PI3K inhibitor, c-kit/Kdr tyrosine kinase inhibitor, Bcr-Abltyrosine kinase inhibitor, VEGFR2 inhibitor, PDGFR-beta inhibitor, KITinhibitor, Flt3 tyrosine kinase inhibitor, PDGF receptor familyinhibitor, Flt3 tyrosine kinase inhibitor, RET tyrosine kinase receptorfamily inhibitor, VEGF-3 receptor antagonist, Raf protein kinase familyinhibitor, angiogenesis inhibitor, Erb2 inhibitor, mTOR inhibitor,IGF-1R antibody, NFkB inhibitor, proteosome inhibitor, chemotherapyagent, and glucose reduction agent.

In some embodiments, the additional therapeutic agent is administered atthe same time as the compound disclosed herein. In some embodiments, theadditional therapeutic agent and the compound disclosed herein areadministered sequentially. In some embodiments, the additionaltherapeutic agent is administered less frequently than the compounddisclosed herein. In some embodiments, the additional therapeutic agentis administered more frequently than the compound disclosed herein. Insome embodiments, the additional therapeutic agent is administered priorthan the administration of the compound disclosed herein. In someembodiments, the additional therapeutic agent is administered after theadministration of the compound disclosed herein.

EXAMPLE Intermediate 1

Step 1: Preparation of 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one

To a stirred solution of methyl 2-oxo-1H-pyridine-3-carboxylate (2 g,13.060 mmol, 1.00 equiv) in THF (20 mL) was added MeMgBr in THF (32.65mL, 65.300 mmol, 5.00 equiv) dropwise at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 2 h at roomtemperature under nitrogen atmosphere. The reaction was quenched withsaturated NH₄Cl (aq.) (40 mL) at room temperature. The resulting mixturewas extracted with EtOAc (3×20 mL). The combined organic layers werewashed with brine (30 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to afford3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (1.1 g, 54.98%) as a whitesolid. LC-MS: (ES+H, m/z): [M+H]⁺=154.1.

Intermediate 2-4

Step 1: Preparation of ethyl 3,5-difluoropicolinate

A solution of 3,5-difluoropyridine-2-carboxylic acid (50.00 g, 314.28mmol, 1.00 equiv) in ethanol (200 ml) was cooled using an ice bath,followed by the addition of SOCl₂ (50 mL, 689.25 mmol, 2.20 equiv)dropwise at 0° C. The resulting mixture was stirred for 3 h at 60° C.under nitrogen atmosphere. The mixture was allowed to r.t. The resultingmixture was concentrated under vacuum. The residue was purified bysilica gel column chromatography to afford ethyl 3,5-difluoropicolinate(59 g, 100%) as a colorless liquid. LC-MS: (ES+H, m/z): [M+H]⁺=188.1.

Step 2: Preparation of (3,5-difluoropyridin-2-yl)methanol

To a stirred solution of ethyl 3,5-difluoropyridine-2-carboxylate (40.00g, 213.74 mmol, 1.00 equiv) in ethanol (300 ml) was added NaBH₄ (20.22g, 534.34 mmol, 2.50 equiv) in portions at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 30 min at 0° C. undernitrogen atmosphere. The resulting mixture was stirred for additional 2h at room temperature under nitrogen atmosphere. The reaction wasquenched with sat. NH₄Cl (aq.) at 0° C. EtOH was removed under reducedpressure. The aqueous layer was basified to pH 10 with saturated Na₂CO₃(aq., 300 mL), followed by extracted with EtOAc (3×300 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under vacuum to afford(3,5-difluoropyridin-2-yl)methanol (26.6 g, 85.76%) as a colorlessliquid. LC-MS: (ES+H, m/z): [M+H]⁺=146.1.

Step 3: Preparation of 2-(chloromethyl)-3,5-difluoropyridine

To a stirred solution of (3,5-difluoropyridin-2-yl)methanol (34.00 g,234.31 mmol, 1.00 equiv) in DCM (500 mL) was added DMF (160 mg), andthen cooled using ice water bath. To the above mixture was added SOCl₂(40 mL, 551.40 mmol, 2.35 equiv) dropwise under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at room temperature under nitrogenatmosphere. The resulting mixture was concentrated under vacuum toafford 2-(chloromethyl)-3,5-difluoropyridine (34.75 g, 90.68%) as abrown-yellow semi-solid. LC-MS: (ES+H, m/z): [M+H]⁺=164.0. ¹H NMR (400MHz, Chloroform-d) δ 8.35 (d, 1H), 7.28 (td, 1H), 4.73 (d, 2H).

Intermediate 5-8

Step 1: Preparation of 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one

A solution of LiHMDS (3.16 L, 3.16 mol, 1.50 equiv, 1M in THF) in THF(1000 mL) was treated with 2,2,6-trimethyl-1,3-dioxin-4-one (300 g, 2.11mol, 1.00 equiv) for 1 h at −20° C. under nitrogen atmosphere followedby the addition of ZnEt₂ (3.16 L, 3.16 mol, 1.50 equiv, 1M in hexane)dropwise over 2 h at −20° C. The resulting mixture was stirred for 30min at −20° C. under nitrogen atmosphere. To the above mixture was addedacetylimidazole (348.58 g, 3.16 mol, 1.50 equiv) at −10° C. Theresulting mixture was stirred for additional overnight at roomtemperature. The reaction was quenched by the addition of 1 L Water/THF(1:1) at −10° C. The mixture was acidified to pH 1-2 with 2M HCl (aq.).The resulting mixture was extracted with EtOAc (3×5 L). The combinedorganic layers were washed with brine (3×5 L), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (200 g, 51.45%)as a Brown yellow crystal. LC-MS: (ES+H, m/z): [M+H]⁺=185.0. ¹H NMR (400MHz, DMSO-d₆) δ 5.35 (s, 1H), 3.35 (s, 2H), 2.25 (s, 3H), 1.72 (d, 6H).

Step 2: Preparation of2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (22.16 g,120.296 mmol, 1.5 equiv) and 2-bromo-5-methylpyridin-4-amine (15 g,80.197 mmol, 1.00 equiv) in 1,4-dioxane (200 mL) was stirred for 2 h at90° C., to the above mixture was added H₂SO₄ (7.87 g, 80.197 mmol, 1equiv) dropwise at room temperature under air atmosphere. The resultingmixture was stirred for additional 1 h at 90° C. The resulting mixturewas concentrated under reduced pressure. To the resulting mixture wasadded H₂O (40 mL) and the slurry was stirred for 10 min. Theprecipitated solids were collected by filtration and washed with Et₂O(3×10 mL), then dried under vacuum to afford2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one (22.7 g, crude)as a yellow solid. The crude resulting mixture was used in the next stepdirectly without further purification. LC-MS: (ES+H, m/z): [M+H]⁺=294.9.

Step 3:2′-chloro-4-[(4-methoxyphenyl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one (42.00 g,142.307 mmol, 1 equiv) and 2-(chloromethyl)-3,5-difluoropyridine (46.55g, 284.614 mmol, 2 equiv) in DMF (450 mL) were added K₂CO₃ (98.34 g,711.535 mmol, 5.00 equiv) and 18-Crown-6(3.76 g, 14.231 mmol, 0.10equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 2 h at 60° C. under nitrogen atmosphere. Desiredproduct could be detected by LCMS. The reaction mixture was partitionedbetween EA (1000 mL) and water (500 mL). The organic layer was washedwith water (500 mL) and brine (500 mL), and then dried over Na₂SO₄. Thesolution was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to afford2′-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(48.5 g, 80.72%) as a yellow oil. LC-MS: (ES+H, m/z): [M+H]⁺=424.0.

Step 4: Preparation of2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(12 g, 28.421 mmol, 1 equiv) and NCS (3.79 g, 28.421 mmol, 1 equiv) in2-Propanol (21 mL) were added 2,2-dichloroacetic acid (1.2 mL, 2.870mmol, 0.10 equiv) dropwise at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 2 h at 60° C. undernitrogen atmosphere. The precipitated solids were collected byfiltration and washed with 2-propanol to afford2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(7.40 g, 57.02%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=457.9. ¹HNMR (300 MHz, DMSO-d₆) δ 8.60 (d, J=2.4 Hz, 1H), 8.52 (s, 1H), 8.10(ddd, J=10.0, 8.9, 2.4 Hz, 1H), 7.81 (s, 1H), 6.80 (s, 1H), 5.48 (d,J=2.0 Hz, 2H), 1.98-1.94 (m, 6H).

Intermediate 9-11

Step 1: Preparation of ethyl 5-chloro-3-fluoropyridine-2-carboxylate

A solution of 5-chloro-3-fluoropyridine-2-carboxylic acid (2.00 g, 11.39mmol, 1.00 equiv) in EtOH (4 mL) was cooled using an ice bath, followedby the addition of H₂SO₄ (2.00 mL) dropwise at 0° C. The resultingmixture was stirred overnight at 50° C. under nitrogen atmosphere. Themixture was allowed to r.t. The resulting mixture was diluted with H₂O(10 mL). The mixture was basified to pH 9 with Na₂CO₃. The resultingmixture was extracted with EA (3×50 mL). The combined organic layerswere washed with brine (2×50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure toafford ethyl 5-chloro-3-fluoropyridine-2-carboxylate (2.10 g, 90.53%) asa yellow liquid. LC-MS: (ES+H, m/z): [M+H]⁺=204.1.

Step 2: Preparation of (5-chloro-3-fluoropyridin-2-yl)methanol

To a stirred solution of ethyl 5-chloro-3-fluoropyridine-2-carboxylate(2.10 g, 10.31 mmol, 1.00 equiv) in EtOH (4 mL) was added NaBH₄ (0.98 g,25.90 mmol, 2.51 equiv) in portions at 0° C. under nitrogen atmosphere.The resulting mixture was stirred for 30 min at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for additional 2 h at roomtemperature under nitrogen atmosphere. The reaction was quenched withsat. NH₄Cl (aq.) at 0° C. EtOH was removed under reduced pressure. Theaqueous layer was basified to pH 10 with saturated Na₂CO₃ (aq.),followed by extracted with EA (3×100 mL). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated under vacuum to afford(5-chloro-3-fluoropyridin-2-yl)methanol (1.50 g, 90.02%) as a yellowsolid. LC-MS: (ES+H, m/z): [M+H]⁺=162.1.

Step 3: Preparation of 5-chloro-2-(chloromethyl)-3-fluoropyridine

To a stirred solution of (5-chloro-3-fluoropyridin-2-yl)methanol (1.45g, 8.97 mmol, 1.00 equiv) in DCM (2 mL) was added DMF (0.66 g, 8.97mmol, 1.00 equiv), and then cooled using ice water bath. To the abovemixture was added SOCl₂ (1.00 mL, 13.78 mmol, 1.54 equiv) dropwise undernitrogen atmosphere. The resulting mixture was stirred for 2 h at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under vacuum to afford5-chloro-2-(chloromethyl)-3-fluoropyridine (2.00 g, crude) as a brownyellow semi-solid. The crude product was used in the next step directlywithout further purification. LC-MS: (ES+H, m/z): [M+H]⁺=180.1.

Intermediate 12-14

Step 1: Preparation of ethyl 3-chloro-5-fluoropyridine-2-carboxylate

A solution of 3-chloro-5-fluoropyridine-2-carboxylic acid (4.50 g, 25.63mmol, 1.00 equiv) in EtOH (100 mL) was cooled with an ice bath. To theabove mixture was added SOCl₂ (6.13 g, 51.53 mmol, 2.01 equiv) dropwiseover 3 min at 0° C. The resulting mixture was stirred for additional 3 hat room temperature. The mixture was allowed to r.t. The resultingmixture was concentrated under vacuum. The residue was purified bysilica gel column chromatography to afford ethyl3-chloro-5-fluoropyridine-2-carboxylate (4.40 g, 84.29%) as a colorlessliquid. LC-MS: (ES+H, m/z): [M+H]⁺=203.9.

Step 2: Preparation of (3-chloro-5-fluoropyridin-2-yl)methanol

To a stirred solution of ethyl 3-chloro-5-fluoropyridine-2-carboxylate(2.10 g, 10.31 mmol, 1.00 equiv) in EtOH (30 mL) was added NaBH₄ (0.98g, 25.90 mmol, 2.51 equiv) in portions at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 30 min at 0° C. undernitrogen atmosphere. The resulting mixture was stirred for additional 2h at room temperature under nitrogen atmosphere. The reaction wasquenched with sat. NH₄Cl (aq.) at 0° C. The resulting mixture wasconcentrated under reduced pressure to remove EtOH, then extracted withEA (3×30 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder vacuum to afford (3-chloro-5-fluoropyridin-2-yl)methanol (2 g,95.24%) as a yellow oil. LC-MS: (ES+H, m/z): [M+H]⁺=162.0.

Step 3: Preparation of 3-chloro-2-(chloromethyl)-5-fluoropyridine

To a stirred solution of (3-chloro-5-fluoropyridin-2-yl)methanol (2.10g, 12.99 mmol, 1.00 equiv) in DCM (30 mL) was added DMF (0.1 mL, 1.30mmol, 0.10 equiv) at 0 under nitrogen atmosphere. The SOCl₂ (2.3 mL,32.49 mmol, 2.50 equiv) was added dropwise under nitrogen atmosphere.The resulting mixture was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum, to afford3-chloro-2-(chloromethyl)-5-fluoropyridine (2.00 g, crude) as a brownyellow oil. The crude product was used in the next step directly withoutfurther purification. LC-MS: (ES+H, m/z): [M+H]⁺=179.90.

Intermediate 15-18

Step 1: Preparation of (3,5-difluoropyridin-2-yl)methan-d2-ol

To a stirred solution of ethyl 5-chloro-3-fluoropyridine-2-carboxylate(500.00 g, 2671.71 mmol, 1.00 equiv) in CD₃OD (500 mL) and THF (1000 mL)was added sodium (H)boranuide (111.84 g, 2671.71 mmol, 1.00 equiv) inportions at 0° C. under nitrogen air. The resulting mixture was stirredfor 2 hours at room temperature under nitrogen atmosphere. The resultingmixture was quenched by the addition of D₂O (200 mL) at 0° C. andstirred for 30 min at 0° C. The mixture was diluted with EtOAc (2000 mL)and washed with water (2000 ml) and brine (2000 ml). The organic layerswere dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure, to afford(3,5-difluoropyridin-2-yl)methan-d2-ol methanol (360.00 g, 91.5%) as ayellow oil. LC-MS: (ES+H, m/z): [M+H]⁺=148.1. ¹H NMR (300 MHz, DMSO-d₆)δ 8.44 (d, 1H), 7.88 (ddd, 1H), 5.37 (s, 1H).

Step 2: Preparation of 2-(chloromethyl-d2)-3,5-difluoropyridine

To a stirred solution of (3,5-difluoropyridin-2-yl)methan-d2-ol (300.00g, 2039.13 mmol, 1.00 equiv) in DCM (1000 mL) was added DMF (14.91 g,203.91 mmol, 0.10 equiv) and SOCl₂ (606.44 g, 5097.84 mmol, 2.50 equiv)dropwise under nitrogen atmosphere at 0. The resulting mixture wasstirred for 2 h at room temperature under nitrogen atmosphere. Theresulting mixture was concentrated under vacuum to afford2-(chloromethyl-d2)-3,5-difluoropyridine (320.00 g, 94.7%) as a yellowoil which was used directly in next step without further purification.LC-MS: (ES+H, m/z): [M+H]⁺=166.1. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d,1H), 8.04-7.93 (m, 1H).

Step 3: Preparation of2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one (100.00 g,338.82 mmol, 1.00 equiv), 18-Crown-6 (5.37 g, 3.00 mmol, 0.40 equiv) andK₂CO₃ (42.14 g, 304.94 mmol, 3.00 equiv) in DMF (200 mL) was added2-(chloromethyl-d2)-3,5-difluoropyridine (27.75 g, 152.47 mmol, 1.50equiv) at r.t. The resulting mixture was stirred for 2.5 h at 60° C.under nitrogen atmosphere. The resulting mixture was filtered, thefilter cake was washed with EtOAc (3×500 mL). The filtrate was dilutedwith EA (3000 mL). The resulting mixture was washed with brine (3×2000mL) and water (5×2000 mL). The organic layer was dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by trituration with Et₂O (3×250 ml)and dried under reduced pressure to afford2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(90 g, 62.8%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=424.0. ¹H NMR(300 MHz, DMSO-d₆) δ 8.59 (d, 1H), 8.48 (s, 1H), 8.08 (ddd, 1H), 7.73(s, 1H), 6.13 (dd, 1H), 6.03 (d, 1H), 1.97 (s, 3H), 1.85 (s, 3H).

Step 4: Preparation of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

To a stirred solution of2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(100.00 g, 235.71 mmol, 1.00 equiv) and NCS (37.77 g, 282.85 mmol, 1.20equiv) in IPA (500 mL) was added 2,2-dichloroacetic acid (3.04 g, 23.57mmol, 0.10 equiv) dropwise at room temperature. The resulting mixturewas stirred for 1 h at 60° C. under nitrogen atmosphere. The mixture wasallowed to cool down to r.t. The precipitated solids were collected byfiltration and washed with cold IPA (4×30 mL), to afford2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(60.00 g, 55.5%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=458.0. ¹HNMR 300 MHz, DMSO-d₆) δ 8.60 (d, 1H), 8.52 (s, 1H), 8.10 (ddd, 1H), 7.81(s, 1H), 6.80 (d, 1H), 1.96 (s, 6H).

Intermediate 19

Step 1: Preparation of 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one

To a stirred solution of methyl 3-oxo-4H-pyrazine-2-carboxylate (500 mg,3.24 mmol, 1.00 equiv) in THF (30 mL) was added bromo(methyl)magnesium(32 mL, 32.44 mmol, 10.00 equiv) dropwise at −5° C. under N2 atmosphere.The resulting mixture was stirred for 2 h at r.t. under N₂ atmosphere.The reaction was quenched by the addition of saturated NH₄Cl (10 mL) at0° C. The resulting mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure to afford 3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (350 mg,crude) as a yellow solid. LC-MS: (ES+H, m/z): [M+H]⁺=155.3.

Intermediate 20-23

Step 1: Preparation of ethyl 5-chloro-3-fluoropyridine-2-carboxylate

To a stirred mixture of 2-bromo-5-chloro-3-fluoropyridine (50.00 g,237.60 mmol, 1.00 equiv) and Pd(dppf)Cl₂ (8.69 g, 11.88 mmol, 0.05equiv) in EtOH (250 ml) were added NEt₃ (72.13 g, 712.82 mmol, 3.00equiv) at room temperature. The resulting mixture was stirred for 6 h at80° C. under carbon monoxide atmosphere (50 atm). The mixture wasallowed to room temperature. The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to afford ethyl 5-chloro-3-fluoropyridine-2-carboxylate(36.40 g, 75.24%) as a yellow green liquid. LC-MS: (ES+H, m/z):[M+H]⁺=204.2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (dd, 1H), 8.24 (dd, 1H),4.36 (q, 2H), 1.32 (t, 3H).

Step 2: Preparation of 5-chloro-3-fluoropyridin-2-yl)(2H2)methanol

To a stirred solution of ethyl 5-chloro-3-fluoropyridine-2-carboxylate(42.00 g, 206.28 mmol, 1.00 equiv) and CaCl₂ (68.68 g, 618.85 mmol, 3.00equiv) in solution of CD₃OD (200 mL) and THF (400 mL) were added sodiumborodeuteride (17.27 g, 412.57 mmol, 2.00 equiv) in portions at 0° C.under nitrogen atmosphere. The resulting mixture was stirred for 3 h atroom temperature under nitrogen atmosphere. The resulting mixture wasdiluted with EtOAc (500 mL). Diatomaceous earth (100 g) was added to thereaction solvent and the resulting mixture was stirred for 10 min. Theresulting mixture was filtered, the filter cake was washed with EtOAc(3×1 L). The filtrate was quenched by the addition of D₂O (35 mL) at 0°C. And washed with brine (2×500 ml). The organic layers were dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. To afford (5-chloro-3-fluoropyridin-2-yl)(2H2)methanol(23.60 g, 69.94%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=164.2. ¹HNMR (300 MHz, DMSO-d₆) δ 8.48 (dd, 1H), 8.06 (dd, 1H), 5.41 (s, 1H).

Step 3: Preparation of 5-chloro-2-[chloro(²H2)methyl]-3-fluoropyridine

To a stirred solution of (5-chloro-3-fluoropyridin-2-yl)(2H2)methanol(23.60 g, 144.28 mmol, 1.00 equiv) and DMF (1.05 g, 14.42 mmol, 0.10equiv) in DCM (200 mL) were added SOCl₂ (42.91 g, 360.70 mmol, 2.50equiv) dropwise at 0° C. under nitrogen atmosphere. The resultingmixture was stirred for 2 h at room temperature under nitrogenatmosphere. The resulting mixture was concentrated under vacuum. Toafford 5-chloro-2-[chloro(2H2)methyl]-3-fluoropyridine (26.30 g, 100%)as a brown oil. LC-MS: (ES+H, m/z): [M+H]⁺=182.1. ¹H NMR (300 MHz,DMSO-d₆) δ 8.53 (dd, 1H), 8.18 (dd, 1H).

Step 4: Preparation of2′-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one (30.00 g, 101.64mmol, 1.00 equiv), 5-chloro-2-[chloro(2H2)methyl]-3-fluoropyridine(27.75 g, 152.47 mmol, 1.50 equiv), 18-Crown-6 (5.37 g, 20.33 mmol, 0.20equiv) and K₂CO₃ (42.14 g, 304.94 mmol, 3.00 equiv) in DMF (200 mL). Theresulting mixture was stirred for 2.5 h at 60° C. under nitrogenatmosphere. The mixture was allowed to room temperature. The resultingmixture was diluted with EA (2 L). The resulting mixture was washed withwater (5×100 mL), and brine (500 mL). The organic layer dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to afford2′-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(30.91 g, 69.00%) as a white solid. LC-MS: (ES+H, m/z):[M+H]⁺=440.1/442.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (dd, 1H), 8.47 (s,1H), 8.22 (dd, 1H), 7.72 (s, 1H), 6.13 (s, 1H), 6.01 (d, 1H), 1.96 (s,3H), 1.85 (s, 3H).

Step 5: Preparation of2′-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred solution of2′-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(30.00 g, 68.07 mmol, 1.00 equiv) and NCS (10.91 g, 81.69 mmol, 1.20equiv) in IPA (200 mL) was added 2,2-dichloroacetic acid (0.88 g, 6.80mmol, 0.10 equiv) dropwise at room temperature under air atmosphere. Theresulting mixture was stirred for 1 h at 60° C. under nitrogenatmosphere. The mixture was allowed to cool down to 0° C. Theprecipitated solids were collected by filtration and washed with coldIPA (3×20 mL). To afford2′-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(24.00 g, 74.20%) as a white solid. LC-MS: (ES+H, m/z):[M+H]⁺=474.0/476.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (dd, 1H), 8.52 (s,1H), 8.23 (dd, 1H), 7.80 (s, 1H), 6.78 (d, 1H), 1.97 (s, 3H), 1.96 (s,3H).

Intermediate 24-27

Step 1: Preparation of ethyl 3-chloro-5-fluoropyridine-2-carboxylate

To a stirred mixture of 2,3-dichloro-5-fluoropyridine (50.00 g, 301.24mmol, 1.00 equiv) and Pd(dppf)Cl₂ (4.41 g, 6.02 mmol, 0.02 equiv) inEtOH (250 ml) were added Et₃N (72.13 g, 712.82 mmol, 3.00 equiv)dropwise at room temperature. The resulting mixture was stirred for 18 hat 100° C. under carbon monoxide atmosphere (50 atm). The mixture wasallowed to room temperature. The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to afford ethyl 3-chloro-5-fluoropyridine-2-carboxylate(33.00 g, 53.80%) as a colorless liquid. LC-MS: (ES+H, m/z):[M+H]⁺=204.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (d, 1H), 8.29 (dd, 1H),4.42 (q, 2H), 1.36 (t, 3H).

Step 2: Preparation of (3-chloro-5-fluoropyridin-2-yl)methan-d2-ol

To a stirred solution of ethyl 3-chloro-5-fluoropyridine-2-carboxylate(84.00 g, 412.57 mmol, 1.00 equiv) and CaCl₂ (91.57 g, 825.14 mmol, 2.00equiv) in solution of CD₃OD (500 mL) and THF (500 mL) were added Sodiumborodeuteride (51.81 g, 1237.72 mmol, 3.00 equiv) in portions at 0° C.under nitrogen atmosphere. The resulting mixture was stirred for 2 h atr.t. under nitrogen atmosphere. The resulting mixture was diluted withEtOAc (500 mL). Diatomaceous earth (100 g) was added to the reactionsolvent. The resulting mixture was filtered, the filter cake was washedwith EtOAc (3×1 L). The filtrate was quenched by the addition of D₂O (50mL) at 0° C. and washed with brine (500 ml). The organic layers weredried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure, to afford(3-chloro-5-fluoropyridin-2-yl)methan-d2-ol (46.00 g, 68.16%) as acolorless liquid. LC-MS: (ES+H, m/z): [M+H]⁺=164.0. ¹H NMR (300 MHz,DMSO-d₆) δ 8.53 (d, 1H), 8.01 (dd, 1H), 5.22 (br, 1H).

Step 3: Preparation of 3-chloro-2-(chloromethyl-d2)-5-fluoropyridine

To a stirred solution of (3-chloro-5-fluoropyridin-2-yl)methan-d2-ol(46.00 g, 281.22 mmol, 1.00 equiv) and DMF (2.18 mL, 28.12 mmol, 0.1equiv) in DCM (200 mL) were added SOCl₂ (40.80 mL, 562.45 mmol, 2.00equiv) dropwise at 0° C. under nitrogen atmosphere. The resultingmixture was stirred for 2 h at r.t. under nitrogen atmosphere. Theresulting mixture was concentrated under vacuum to afford3-chloro-2-(chloromethyl-d2)-5-fluoropyridine (31.00 g, 60.56%) as abrown yellow liquid. LC-MS: (ES+H, m/z): [M+H]⁺=182.0. ¹H NMR (300 MHz,DMSO-d₆) δ 8.59 (d, 1H), 8.16 (dd, 1H).

Step 4: Preparation of2′-bromo-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one (25.00 g, 84.70mmol, 1.00 equiv), 18-Crown-6 (4.48 g, 16.94 mmol, 0.2 equiv) and K₂CO₃(58.53 g, 423.53 mmol, 5.00 equiv) in DMF (250 mL) was added3-chloro-2-(chloromethyl-d2)-5-fluoropyridine (30.84 g, 169.41 mmol,2.00 equiv) at r.t. The resulting mixture was stirred for 2 h at 60° C.under nitrogen atmosphere. The mixture was allowed to room temperature.The resulting mixture was diluted with EA (2000 mL). The resultingmixture was washed with brine (5×500 mL). The organic layer dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to afford2′-bromo-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(30.00 g, 56.26%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=440.0. ¹HNMR (300 MHz, DMSO-d₆) δ 8.67 (d, 1H), 8.48 (s, 1H), 8.23 (dd, 1H), 7.73(s, 1H), 6.14 (dd, 1H), 6.01 (d, 1H), 1.97 (s, 3H), 1.86 (s, 3H).

Step 5: Preparation of2′-bromo-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

To a stirred solution of2′-bromo-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(30.00 g, 68.07 mmol, 1.00 equiv) and NCS (11.82 g, 88.49 mmol, 1.30equiv) in IPA (300 mL) was added 2,2-dichloroacetic acid (0.88 g, 6.80mmol, 0.10 equiv) dropwise at room temperature. The resulting mixturewas stirred for 1 h at 60° C. under nitrogen atmosphere. The mixture wasallowed to cool down to r.t. The precipitated solids were collected byfiltration and washed with cold IPA (3×40 mL), to afford2′-bromo-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(17.52 g, 54.17%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=476.05.¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (d, 1H), 8.55-8.50 (m, 1H), 8.25 (dd,1H), 7.81 (s, intel H), 6.77 (d, 1H), 1.97 (s, 3H), 1.95 (s, 3H).

Example 1A, 1B

Step 1: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(500 mg, 1.095 mmol, 1 equiv),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (311.49 mg, 2.190 mmol, 2equiv) and CuI (417.04 mg, 2.190 mmol, 2 equiv) in dioxane (20 mL) wereadded K₂CO₃ (302.64 mg, 2.190 mmol, 2 equiv) at room temperature undernitrogen atmosphere. The resulting mixture was stirred for overnight at80° C. under nitrogen atmosphere. The mixture was allowed to cool downto room temperature. The reaction was quenched with saturating NH₄Cl(aq.) (50 mL) at room temperature. The resulting mixture was extractedwith EtOAc (3×25 mL). The combined organic layers were washed with brine(40 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(250 mg, 43.17%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=529.1. ¹HNMR (300 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.64-8.00 (m, 1H),7.86 (d, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 6.81 (s, 1H), 6.43 (t, 1H),5.48 (s, 2H), 5.23 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.47 (d, 6H).

Step 2: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(250 mg, 0.473 mmol, 1 equiv) was separated by Prep-HPLC to affordrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 1A, 48.0 mg, 97.6%, ee=100.0%) andrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 1B, 51.4 mg, 98.7%, ee=99.6%) as a white solid.

Example 1A: LC-MS: (ES+H, m/z): [M+H]⁺=529.00. ¹H NMR (300 MHz, DMSO-d₆)δ 8.69 (s, 1H), 8.61 (d, 1H), 8.17-8.03 (m, 1H), 7.86 (m, 1H), 7.79 (s,1H), 7.70 (m, 1H), 6.81 (m, 1H), 6.43 (t, 1H), 5.48 (d, 2H), 5.23 (s,1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.47 (S, 3H), 1.46 (S, 3H). ¹⁹F NMR(377 MHz, DMSO-d₆) δ−120.16, −120.18, −122.36, −122.38. [a]_(D) ²⁵=−171(C=1, MeOH).

Example 1B: LC-MS: (ES+H, m/z): [M+H]⁺=529.10. ¹H NMR (400 MHz, DMSO-d₆)δ 8.68 (s, 1H), 8.60 (d, 1H), 8.09 (m, 1H), 7.85 (m, 1H), 7.78 (s, 1H),7.69 (m, 1H), 6.82-6.77 (m, 1H), 6.42 (t, 1H), 5.48 (d, 2H), 5.22 (s,1H), 2.07 (s, 3H), 2.01 (s, 3H), 1.47 (S, 3H), 1.46 (S, 3H). ¹⁹F NMR(377 MHz, DMSO-d₆) δ−120.16, −120.18, −122.35, −122.37. [a]_(D)²⁵=+174.8 (C=1, MeOH).

Example 2A, 2B

Step 1: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}-6-methylpyridin-2-one

To a stirred mixture of1-(5-bromo-2-methylphenyl)-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methylpyridin-2-one(300 mg, 0.65 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (200 mg, 1.31 mmol, 2.00equiv), CuI (250.77 mg, 1.31 mmol, 2.00 equiv) and(1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (187.29 mg, 1.31 mmol,2.00 equiv) in 1,4-dioxane (5 mL) was added K₂CO₃ (181.98 mg, 1.31 mmol,2.00 equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 3 h at 80° C. under nitrogen atmosphere. Themixture was allowed to cool down to room temperature. The reaction wasquenched with sat. NH₄Cl (aq.) (50 mL) at room temperature. Theresulting mixture was extracted with EtOAc (2×25 mL). The combinedorganic layers were washed with brine (30 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by reverse combi-flash chromatographyto afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}-6-methylpyridin-2-one(140 mg, 40.28%) as alight yellow solid. LC-MS: (ES+H, m z):[M+H]⁺=528.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, 1H), 8.12-8.06 (m,1H), 7.66-7.64 (m, 1H), 7.63-7.60 (m, 1H), 7.54 (d, 1H), 7.48-7.44 (m,1H), 7.37 (d, 1H), 6.77-6.72 (m, 1H), 6.39-6.34 (m, 1H), 5.46 (d, 2H),5.29 (s, 1H), 2.03 (s, 3H), 2.16 (s, 3H), 1.46 (s, 6H).

Step 5: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}-6-methylpyridin-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}-6-methylpyridin-2-one

The race-mixture (140 mg) was separated by Prep-HPLC to affordrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}-6-methylpyridin-2-one(Example 2A, 68.7 mg, ee=100.00%) as alight yellow solid. andrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-1-{5-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-2-methylphenyl}-6-methylpyridin-2-one(Example 2B, 38.8 mg, ee=100.00%) as alight yellow solid.

Example 2A: LC-MS: (ES+H, m z): [M+H]⁺=528.25. ¹H NMR (300 MHz, DMSO-d₆)δ 8.60 (d, 1H), 8.15-8.05 (m, 1H), 7.70-7.60 (m, 2H), 7.55 (d, 1H),7.49-7.44 (m, 1H), 7.38 (d, 1H), 6.75 (s, 1H), 6.40-6.34 (m, 1H), 5.47(d, 2H), 5.30 (s, 1H), 2.03 (s, 3H), 2.16 (s, 3H), 1.47 (s, 3H), 1.46(s, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−120.15, −120.17, −122.39, −122.41.

Example 2B: LC-MS: (ES+H, m z): [M+H]⁺=528.25. ¹H NMR (300 MHz, DMSO-d₆)δ 8.60 (d, 1H), 8.15-8.05 (m, 1H), 7.70-7.60 (m, 2H), 7.55 (d, 1H),7.49-7.44 (m, 1H), 7.38 (d, 1H), 6.75 (s, 1H), 6.40-6.34 (m, 1H), 5.47(d, 2H), 5.30 (s, 1H), 2.03 (s, 3H), 2.16 (s, 3H), 1.47 (s, 3H), 1.46(s, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−120.15, −120.17, −122.39, −122.41.

Example 3A, 3B

Step 1: Preparation of 1-(imidazol-1-yl)-2-methoxyethanone

To a stirred solution of imidazole (25.09 g, 368.60 mmol, 2.00 equiv) inTHF (200 mL) was added methoxyacetyl chloride (20.00 g, 184.30 mmol,1.00 equiv) dropwise at 0° C. under nitrogen atmosphere. The resultingmixture was stirred for 3 h at 0° C. under nitrogen atmosphere. Thereaction was monitored by LCMS. The resulting mixture was filtered, thefilter cake was washed with THF (3×50 mL). The filtrate was concentratedunder reduced pressure to afford product1-(imidazol-1-yl)-2-methoxyethanone (16.00 g, 61.95%) as yellow oil. ¹HNMR (300 MHz, Chloroform-d) δ7.52 (t, 1H), 7.22 (d, 1H), 7.15-7.05 (m,1H), 4.55 (s, 2H), 3.51 (s, 3H).

Step 2: Preparation of6-(3-methoxy-2-oxopropyl)-2,2-dimethyl-1,3-dioxin-4-one

Into a 1 L 3-necked round-bottom flask were added THF (50 mL) at roomtemperature, then LiHMDS (56.98 mL, 1M in THF, 56.98 mmol, 1.50 equiv)at −20° C. under nitrogen atmosphere. To the above solution was added2,2,6-trimethyl-1,3-dioxin-4-one (5.40 g, 37.99 mmol, 1.00 equiv)dropwise at −20° C. under nitrogen atmosphere. The resulting mixture wasstirred for 1 h at −20° C. To the stirred mixture was added diethylzinc(56.98 mL, 56.98 mmol, 1.50 equiv) dropwise at −20° C. under nitrogenatmosphere. Slowly raise the temperature of the reaction to −10 and stirfor 10 min. 1-(imidazol-1-yl)-2-methoxyethanone (7.99 g, 56.98 mmol,1.50 equiv) was then added to the above mixture at −10° C. undernitrogen atmosphere. The resulting mixture was stirred for additional 2h at room temperature. The reaction was quenched by the addition ofwater (50 mL) at −20° C. The mixture was acidified to pH 6 with HCl(aq.). The resulting mixture was diluted with EtOAc (200 mL). Theresulting mixture was washed with brine (200 mL). The organic layerswere dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to afford6-(3-methoxy-2-oxopropyl)-2,2-dimethyl-1,3-dioxin-4-one (4.68 g, 57.51%)as a yellow liquid. LC-MS: (ES+H, m/z): [M+H]⁺=215.1. ¹H NMR (300 MHz,DMSO-d₆) δ 5.47 (s, 1H), 4.14 (s, 2H), 3.53 (s, 2H), 3.30 (s, 3H), 1.64(s, 6H).

Step 3: Preparation of2′-chloro-4-hydroxy-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one

To a stirred mixture of6-(3-methoxy-2-oxopropyl)-2,2-dimethyl-1,3-dioxin-4-one (4.00 g, 18.67mmol, 1.00 equiv) in 1,4-dioxane (40 mL) were added2-chloro-5-methylpyridin-4-amine (2.66 g, 18.67 mmol, 1.00 equiv) atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred for 3 h at 90° C. under nitrogen atmosphere. The resultingmixture were added H₂SO₄ (1.83 g, 18.67 mmol, 1.00 equiv) dropwise atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred for 1 h at 90° C. under nitrogen atmosphere. Desired productcould be detected. The mixture was allowed to cool down to roomtemperature. To the above mixture was added H₂O (3 mL), followed byaddition of a large amount of ethyl ether and then stirred for 15 min atroom temperature, The precipitated solids were collected by filtrationand washed with diethyl ether. The resulting mixture was concentratedunder reduced pressure to afford2′-chloro-4-hydroxy-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one(400 mg, 7.63%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=281.2.

Step 4: Preparation of2′-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-chloro-4-hydroxy-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one(417 mg, 1.49 mmol, 1.00 equiv) and2-(chloromethyl)-3,5-difluoropyridine (486 mg, 2.92 mmol, 2.00 equiv) inDMF (5 mL) were added K₂CO₃ (1.02 g, 7.43 mmol, 5.00 equiv) and18-Crown-6(39 mg, 0.15 mmol, 0.10 equiv) at room temperature undernitrogen atmosphere. The resulting mixture was stirred for 2 h at 60° C.under nitrogen atmosphere. The resulting mixture was diluted with EtOAc(50 mL). The resulting mixture was washed with brine (50 mL). Theorganic layers were dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to afford2′-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one(468 mg, 77.25%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=408.0.

Step 5: Preparation of2′,3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one(418 mg, 1.03 mmol, 1.00 equiv) and NCS (137 mg, 1.03 mmol, 1.00 equiv)in 2-Propanol (2 mL) was added 2,2-dichloroacetic acid (0.01 mL, 0.10mmol, 0.10 equiv) dropwise at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 2 h at 60° C. undernitrogen atmosphere. Desired product could be detected by LCMS. Theresulting mixture was diluted with EtOAc (50 mL). The resulting mixturewas washed with NaHCO₃ (50 mL). The organic layers were dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure to afford2′,3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one(440 mg, 97.07%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=441.9.

Step 6: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′,3-dichloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one(450 mg, 1.02 mmol, 1.00 equiv) and3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (312 mg, 2.04 mmol, 2.00equiv) in 1,4-dioxane (4 mL) were added K₂CO₃ (281 mg, 2.04 mmol, 2.00equiv), CuI (388 mg, 2.04 mmol, 2.00 equiv), NaI (305 mg, 2.04 mmol,2.00 equiv) and (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (289 mg,2.04 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere.The resulting mixture was stirred overnight at 100° C. under nitrogenatmosphere. The resulting mixture was diluted with EtOAc (50 mL). Theresulting mixture was washed with water (3×50 mL). The organic layerswere dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure to afford the crude product (230mg), which was purified by Prep-HPLC to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one(130 mg, 22.86%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=559.2.

Step 7: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-6-(methoxymethyl)-5′-methyl-[1,4′-bipyridin]-2-one

The racemate (130 mg) was separated by Prep-Chiral-HPLC to affordExample 3A (47.1 mg, 99.1%, ee=100%) as a white solid and Example 3B(45.1 mg, 99.1%, ee=97.24%) as a white solid.

Example 3A: LC-MS: (ES+H, m/z): [M+H]⁺=559.1. ¹H NMR (300 MHz, DMSO-d6)δ 8.65 (s, 1H), 8.60 (d, 1H), 8.14-8.06 (m, 1H), 7.87-7.82 (m, 1H), 7.79(s, 1H), 7.72-7.67 (m, 1H), 6.87 (s, 1H), 6.42 (t, 1H), 5.53 (s, 2H),5.23 (s, 1H), 4.12-3.95 (m, 2H), 3.07 (s, 3H), 2.06 (s, 3H), 1.47 (s,6H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.09, −120.11, −122.31, −122.35.

Example 3B: LC-MS: (ES+H, m/z): [M+H]⁺=559.1. ¹H NMR (300 MHz, DMSO-d₆)δ 8.65 (s, 1H), 8.60 (d, 1H), 8.14-8.06 (m, 1H), 7.87-7.82 (m, 1H), 7.79(s, 1H), 7.72-7.67 (m, 1H), 6.87 (s, 1H), 6.42 (t, 1H), 5.53 (s, 3H),5.23 (s, 1H), 4.12-3.95 (m, 2H), 3.07 (s, 3H), 2.06 (s, 3H), 1.47 (s,6H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.09, −120.11, −122.31, −122.35.

Example 4A, Example 4B

Step 1: Preparation of2′-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred solution of2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one (1.00 g, 3.38mmol, 1.00 equiv) and 5-chloro-2-(chloromethyl)-3-fluoropyridine (914mg, 5.08 mmol, 1.50 equiv) in DMF (10 mL) were added 18-Crown-6 (89 mg,0.33 mmol, 0.10 equiv) and K₂CO₃ (1.40 g, 10.16 mmol, 3.00 equiv) atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred overnight at 60° C. under nitrogen atmosphere. The mixture wasallowed to cool down to r.t. The reaction was poured into water (50 mL)at room temperature. The resulting mixture was extracted with EtOAc(3×50 mL). The combined organic layers were washed with brine (5×100mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to afford2′-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(1.30 g, 87.46%) as an off-white solid. LC-MS: (ES+H, m/z):[M+H]⁺=439.9.

Step 2: Preparation of2′-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred solution of2′-bromo-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(500 mg, 1.14 mmol, 1.00 equiv) and NCS (152 mg, 1.14 mmol, 1.00 equiv)in IPA (2.5 mL) was added 2,2-dichloroacetic acid (14 mg, 0.11 mmol,0.10 equiv) dropwise at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at 60° C. under nitrogenatmosphere. The mixture was allowed to cool down to r.t. Theprecipitated solids were collected by filtration and washed with coolIPA (2×10 mL), to afford2′-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(440 mg, 81.59%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=473.9.

Step 3: Preparation of3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(440 mg, 0.93 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (285 mg, 1.86 mmol, 2.00equiv), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (264 mg, 1.86mmol, 2.00 equiv), CuI (44 mg, 0.23 mmol, 0.25 equiv) and K₂CO₃ (257 mg,1.86 mmol, 2.00 equiv) in super dry 1,4-dioxane (5 mL) was stirred for 3h at 100° C. under nitrogen atmosphere. The reaction was poured intowater (50 mL) at room temperature. The resulting mixture was extractedwith EtOAc (3×50 mL). The combined organic layers were washed with brine(100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The crude product (220 mg) waspurified by Prep-HPLC, the pure fraction was concentrated under reducedpressure to afford3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(145 mg, 28.59%) as an off-white solid. LC-MS: (ES+H, m/z):[M+H]⁺=544.8.

Step 4: Preparation ofrel-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one)

The racemate3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(190 mg) was separated by prep-chiral-HPLC, the pure fraction wasconcentrated under vacuum and was lyophilized to afford Example 4A (45.1mg, 98.6% purity, ee=100%) as an off-white solid and Example 4B (50.0mg, 98.9% purity, ee=100%) as an off-white solid.

Example 4A: LC-MS: (ES+H, m/z): [M+H]⁺=545.10. ¹H NMR (400 MHz, DMSO-d₆)δ 8.68 (d, 1H), 8.63-8.60 (m, 1H), 8.27-8.21 (m, 1H), 7.88-7.83 (m, 1H),7.78 (s, 1H), 7.72-7.68 (m, 1H), 6.81-6.75 (m, 1H), 6.45-6.39 (m, 1H),5.50 (d, 2H), 5.22 (s, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.47 (s, 3H),1.46 (s, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−121.60.

Example 4B: LC-MS: (ES+H, m/z): [M+H]⁺=545.10. ¹H NMR (400 MHz, DMSO-d₆)δ 8.68 (d, 1H), 8.62-8.60 (m, 1H), 8.26-8.21 (m, 1H), 7.88-7.83 (m, 1H),7.78 (s, 1H), 7.72-7.68 (m, 1H), 6.79-6.76 (m, 1H), 6.45-6.40 (m, 1H),5.50 (d, 2H), 5.22 (s, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.47 (s, 3H),1.46 (s, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−121.60.

Example 5A, Example 5B

Step 1: Preparation of racemate3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(500 mg, 1.09 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (337 mg, 2.19 mmol, 2.00equiv), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (311 mg, 2.19mmol, 2.00 equiv), K₂CO₃ (302 mg, 2.19 mmol, 2.00 equiv) and CuI (417mg, 2.19 mmol, 2.00 equiv) in 1,4-dioxane (5 mL) was stirred for 2 h at80° C. under nitrogen atmosphere. The resulting mixture was cooled downto r.t. and poured into 10 mL of water. The resulting mixture wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine (50 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to afford crude product,which was further purified by Prep-HPLC to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(160 mg, 27.58%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=530.0.

Step 2: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The racemate (160 mg) was separated by Prep-Chiral-HPLC to affordExample 5A (69.5 mg, 98.2% purity, ee=100%) as white solid and Example5B (56.2 mg, 99.5% purity, ee=100%) as white solid.

Example 5A: LC-MS: (ES+H, m/z): [M+H]⁺=530.2. ¹H NMR (400 MHz, DMSO-d₆)δ 8.74 (s, 1H), 8.60 (d, 1H), 8.15-8.05 (m, 1H), 8.00 (d, 1H), 7.94 (s,1H), 7.47 (d, 1H), 6.81 (s, 1H), 5.49 (d, 2H), 5.12 (s, 1H), 2.10 (s,3H), 2.00 (s, 3H), 1.50 (s, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−120.17,−120.19, −122.36, −122.38.

Example 5B: LC-MS: (ES+H, m/z): [M+H]⁺=530.2. ¹H NMR (400 MHz, DMSO-d₆)δ 8.74 (s, 1H), 8.60 (d, 1H), 8.13-8.06 (m, 1H), 8.00 (d, 1H), 7.94 (s,1H), 7.47 (d, 1H), 6.81 (s, 1H), 5.49 (d, 2H), 5.12 (s, 1H), 2.10 (s,3H), 2.00 (s, 3H), 1.50 (s, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−120.17,−120.19, −122.36, −122.38.

Example 6

Step 1: Preparation of ethyl2-(3-chloro-6-oxopyridazin-1-yl)-2-methylpropanoate

To a stirred solution of 6-chloro-2H-pyridazin-3-one (2.60 g, 19.91mmol, 1.00 equiv) in DMF (50 mL) were added LiHMDS (19.92 mL, 1 mol/L inTHF, 19.91 mmol, 1.00 equiv) dropwise at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 1 h at roomtemperature under nitrogen atmosphere. To the above mixture was addedethyl α-bromoisobutyrate (7.77 g, 39.83 mmol, 2.00 equiv) dropwise atroom temperature. The resulting mixture was stirred overnight at 80° C.The mixture was allowed to cool down to room temperature. The reactionwas quenched with sat. NH₄Cl (aq.) at 0° C., The mixture was acidifiedto pH 6 with CH₃COOH. The resulting mixture was extracted with EtOAc(3×100 mL). The combined organic layers were washed with brine (5×100mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, the pure fraction was concentrated undervacuum to afford ethyl2-(3-chloro-6-oxopyridazin-1-yl)-2-methylpropanoate (800 mg, 16.41%) asa yellow liquid. ¹H NMR (300 MHz, Chloroform-d) δ 7.21 (d, 1H), 6.87 (d,1H), 4.18 (q, 2H), 1.67 (s, 6H), 1.22 (t, 3H).

Step 2-3: Preparation of ethyl2-(3-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2-oxo-[1,4′-bipyridin]-2′-yl}-6-oxopyridazin-1-yl)-2-methylpropanoate

To a stirred mixture of ethyl2-(3-chloro-6-oxopyridazin-1-yl)-2-methylpropanoate (280 mg, 1.14 mmol,1.00 equiv) and bis(pinacolato)diboron (581 mg, 2.28 mmol, 2.00 equiv)in 1,4-dioxane (5 mL) were added XPhos (54 mg, 0.11 mmol, 0.10 equiv),Pd(AcO)₂ (12 mg, 0.05 mmol, 0.05 equiv) and AcOK (336 mg, 3.43 mmol,3.00 equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 2 h at 80° C. under nitrogen atmosphere. Themixture was allowed to cool down to room temperature. The resultingmixture was used in the next step directly without further purification.

To the above mixture was added2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(439 mg, 0.96 mmol, 0.84 equiv), K₂CO₃ (474 mg, 3.43 mmol, 3.00 equiv)and Pd(dppf)Cl₂CH₂Cl₂ (46 mg, 0.05 mmol, 0.05 equiv) and H₂O (1 mL) atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred for 2 h at 80° C. under nitrogen atmosphere. The mixture wasallowed to cool down to room temperature. The resulting mixture waspoured into water (100 mL) at room temperature. The resulting mixturewas extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine (3×50 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, the purefraction was concentrated under vacuum to afford crude product (270 mg).The crude product (100 mg) was purified by Prep-HPLC, the pure fractionwas concentrated under reduced pressure and then lyophilized to affordethyl2-(3-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2-oxo-[1,4′-bipyridin]-2′-yl}-6-oxopyridazin-1-yl)-2-methylpropanoate(56.6 mg, 22.76%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=586.1. ¹HNMR (300 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.61 (d, 1H), 8.38 (d, 1H),8.17-8.04 (m, 2H), 7.13 (d, 1H), 6.82 (s, 1H), 5.49 (s, 2H), 4.08 (q,2H), 2.06 (s, 3H), 1.98 (s, 3H), 1.68 (s, 3H), 1.67 (s, 3H), 1.13 (t,3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.11, −120.14, −122.29, −122.32.

Example 7A, 7B

Step 1: Preparation of2′-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one (3.00 g, 10.16mmol, 1.00 equiv) and 3-chloro-2-(chloromethyl)-5-fluoropyridine (3.64g, 20.22 mmol, 1.99 equiv) in DMF (0.79 mL, 10.16 mmol, 1.00 equiv) wereadded K₂CO₃ (7.02 g, 50.82 mmol, 5.00 equiv) and 18-Crown-6 (806 mg,3.04 mmol, 0.30 equiv) at room temperature under nitrogen atmosphere.The resulting mixture was stirred for 1 h at 60° C. under nitrogenatmosphere. The mixture was allowed to cool down to room temperature.The reaction mixture was diluted with ethyl acetate (100 mL). Theorganic layer was washed with water (100 mL) and brine (100 mL), andthen dried over Na₂SO₄. The solution was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford2′-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(2.00 g, 66.67%) as an off-white solid. LC-MS: (ES+H, m/z):[M+H]⁺=439.9.

Step 2: Preparation of2′-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(2.00 g, 4.55 mmol, 1.00 equiv) and 2,2-dichloroacetic acid (0.06 mL,0.45 mmol, 0.10 equiv) in i-PrOH (10 mL) was added NCS (608 mg, 4.55mmol, 1.00 equiv) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at 60° C. under nitrogenatmosphere. The mixture was allowed to cool down to room temperature.The precipitated solids were collected by filtration and washed withcool IPA (2×5 mL), to afford2′-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(1.50 g, 75%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=473.9.

Step 3: Preparation of3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred solution of2′-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(750 mg, 1.58 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (485.65 mg, 3.17 mmol, 2equiv), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (450 mg, 3.17mmol, 2.00 equiv) and CuI (603 mg, 3.17 mmol, 2.00 equiv) in dioxane (15mL) were added K₂CO₃ (438 mg, 3.17 mmol, 2.00 equiv) at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred overnightat 80° C. under nitrogen atmosphere. The resulting mixture was dilutedwith ethyl acetate (100 mL), then washed with water (2×50 mL) and brine(50 mL), dried over anhydrous Na₂SO₄. After filtration, The resultingmixture was concentrated under reduced pressure. The residue waspurified by reverse flash chromatography to afford3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(600 mg, 80%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=545.0.

Step 4: Preparation ofrel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(190 mg) was isolated by prep-chiral-HPLC, the pure fraction wasconcentrated under vacuum and was lyophilized to affordrel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 7A, 76.3 mg, 96.7% purity, ee=100%) as an off-white solid andrel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 7B, 67.2 mg, 98.4% purity, ee=100%) as an off-white solid.

Example 7A: LC-MS: (ES+H, m/z): [M+H]⁺=545.0. ¹H NMR (300 MHz, DMSO-d₆)δ 8.72-8.65 (m, 2H), 8.25 (dd, 1H), 7.86 (dd, 1H), 7.79 (s, 1H), 7.70(dd, 1H), 6.77 (s, 1H), 6.43 (t, 1H), 5.50 (s, 2H), 5.23 (s, 1H), 2.08(s, 3H), 2.00 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −124.21.

Example 7B: LC-MS: (ES+H, m/z): [M+H]⁺=545.0. ¹H NMR (300 MHz, DMSO-d₆)δ 8.72-8.64 (m, 2H), 8.25 (dd, 1H), 7.86 (dd, 1H), 7.79 (s, 1H), 7.70(dd, 1H), 6.77 (s, 1H), 6.43 (t, 1H), 5.50 (s, 2H), 5.24 (s, 1H), 2.08(s, 3H), 2.00 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −124.19.

Example 8A, 8B

Step 1: Preparation of 3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyridin-2-one

To a stirred mixture of 3-bromo-1H-pyridin-2-one (5.00 g, 28.73 mmol,1.00 equiv) and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(18.11 g, 86.20 mmol, 3.00 equiv) in dioxane (150 mL) and H₂O (30 mL)were added AcOK (8.46 g, 86.20 mmol, 3.00 equiv), Pd(dppf)Cl₂ (4.21 g,5.74 mmol, 0.20 equiv), the resulting mixture was stirred overnight at110° C. under nitrogen atmosphere. The reaction was allowed to cool downto room atmosphere. The resulting mixture was filtered, the filter cakewas washed with EtOAc (3×100 mL). The filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to afford 3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyridin-2-one)(2.60 g, 51.0%) as a yellow solid. LC-MS: (ES+H, m/z): [M+H]⁺=177.9.

Step 2: Preparation of 3-(oxan-4-yl)-1H-pyridin-2-one

A mixture of 3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyridin-2-one (2.00 g,11.28 mmol, 1.00 equiv) and Pd/C (158 mg, 1.12 mmol, 0.10 equiv) in MeOH(100 mL) was stirred for 3 h at room temperature under hydrogenatmosphere. The resulting mixture was filtered, the filter cake waswashed with MeOH (3×50 mL). The filtrate was concentrated under reducedpressure. This resulted in 3-(oxan-4-yl)-1H-pyridin-2-one) (1.80 g,88.9%) as a yellow solid. LC-MS: (ES+H, m/z): [M+H]⁺=180.2.

Step 3: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2′-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4′-bipyridin]-2-one

To a stirred mixture of 3-(oxan-4-yl)-1H-pyridin-2-one (500 mg, 2.79mmol, 2.00 equiv) and2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(637 mg, 1.39 mmol, 1.00 equiv) in dioxane (15 mL) were added CuI (531mg, 2.79 mmol, 2.00 equiv), N1,N2-dimethylcyclohexane-1,2-diamine (396mg, 2.79 mmol, 2.00 equiv) and K₂CO₃ (386 mg, 2.79 mmol, 2.00 equiv),the resulting mixture was stirred at 80° C. for 3 h under nitrogenatmosphere. The resulting mixture was filtered, the filter cake waswashed with EtOAc (3×10 mL). The filtrate was extracted with EtOAc (3×30mL). The combined organic layers were washed with brine (60 mL), driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by Prep-HPLC. Thisresulted in3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2′-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4′-bipyridin]-2-one(547 mg, 70.6%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=555.1.

Step 4: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2′-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2′-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4′-bipyridin]-2-one

3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2′-[3-(oxan-4-yl)-2-oxopyridin-1-yl]-[1,4′-bipyridin]-2-one(260 mg) was separated by prep-chiral-HPLC to afford Example 8A (68.5mg, 98.5% purity, ee=100.0%) and Example 8B (56.6 mg, 99.2% purity,ee=100.0%) as a white solid.

Example 8A: LC-MS: (ES+H, m/z): [M+H]⁺=555.05. ¹H NMR (300 MHz, DMSO-d₆)δ 8.68 (s, 1H), 8.61 (d, 1H), 8.13-8.10 (m, 1H), 7.86 (dd, 1H), 7.80 (s,1H), 7.40-7.34 (m, 1H), 6.81 (s, 1H), 6.39 (t, 1H), 5.49 (d, 2H), 3.94(d, 2H), 3.47-3.37 (m, 2H), 2.99-2.92 (m, 1H), 2.08 (s, 3H), 2.02 (s,3H), 1.69-1.81 (m, 2H), 1.62-1.52 (m, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−120.16, −120.19, −122.36, −122.38.

Example 8B: LC-MS: (ES+H, m/z): [M+H]⁺=555.00. ¹H NMR (300 MHz, DMSO-d₆)δ 8.68 (s, 1H), 8.60 (d, 1H), 8.13-8.06 (m, 1H), 7.87 (dd, 1H), 7.80 (s,1H), 7.38-7.36 (m, 1H), 6.81 (s, 1H), 6.39 (t 1H), 5.49 (d, 2H), 3.94(d, 2H), 3.51-3.33 (m, 2H), 2.95 (t, 1H), 2.08 (s, 3H), 2.01 (s, 3H),1.82-1.39 (m, 4H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.16, −120.19,−122.36, −122.38.

Example 9A, 9B

Step 1: Preparation of 4-(2-hydroxypropan-2-yl)-2H-pyridazin-3-one

To a stirred solution of ethyl 3-oxo-2H-pyridazine-4-carboxylate (1.00g, 5.94 mmol, 1.00 equiv) in THF (10 ml) were added CH₃MgBr (19.80 mL, 3M in 2-MeTHF, 59.40 mmol, 10.00 equiv) dropwise at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 2 h at 0° C. undernitrogen atmosphere. The reaction was quenched with sat. NH₄Cl (aq.) at0° C. The resulting mixture was extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure.The crude product was used in the next step directly without furtherpurification. LC-MS: (ES+H, m/z): [M+H]⁺=155.3.

Step 2: Preparation ofbis(3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one)

To a mixture of 4-(2-hydroxypropan-2-yl)-2H-pyridazin-3-one (1.00 g,6.49 mmol, 1.00 equiv),2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(3.26 g, 7.12 mmol, 1.10 equiv),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.92 g, 6.48 mmol, 1.00equiv), CuI (1.24 g, 6.48 mmol, 1.00 equiv) and K₂CO₃ (1.80 g, 12.98mmol, 2.00 equiv) in dioxane (20 mL) at room temperature. The mixturewas heated at 80° C. for 3 h. The mixture was allowed to cool down toroom temperature. The resulting mixture was diluted with water (100 mL).Then extracted with EtOAc (3×100 mL). The combined organic layers werewashed with brine (100 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(0.68 g, 19.78%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=529.9. ¹HNMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.40 (d, 1H), 8.00 (d, 1H),7.55 (s, 1H), 7.36-7.27 (m, 1H), 7.25 (d, 1H), 6.41 (d, 1H), 5.41 (d,2H), 5.14-4.43 (m, 1H), 2.19 (s, 3H), 2.07 (s, 3H), 1.60 (s, 3H), 1.59(s, 3H).

Step 3: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The rac-mixture (150 mg) was separated by Prep-Chiral HPLC to affordrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 9A, 45.9 mg, ee=100%) as an off-white solid andrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyridazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 9B, 50.8 mg, ee=99.32%)

Example 9A: LC-MS: (ES+H, m/z): [M+H]⁺=530.0. ¹H NMR (300 MHz, DMSO-d₆)δ 8.69 (s, 1H), 8.60 (d, 1H), 8.15-8.08 (m, 1H), 8.07 (d, 1H), 7.69 (s,1H), 7.59 (d, 1H), 6.81 (d, 1H), 5.48 (d, 2H), 5.40 (s, 1H), 2.09 (s,3H), 1.98 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −120.15, −120.18, −122.35, −122.37.

Example 9B: LC-MS: (ES+H, m/z): [M+H]⁺=530.0. ¹H NMR (300 MHz, DMSO-d₆)δ 8.69 (s, 1H), 8.60 (d, 1H), 8.15-8.08 (m, 1H), 8.07 (d, 1H), 7.69 (s,1H), 7.59 (d, 1H), 6.81 (d, 1H), 5.48 (d, 2H), 5.40 (s, 1H), 2.09 (s,3H), 1.98 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −120.15, −120.18, −122.35, −122.37.

Example 10A, 10B

Step 1: Preparation of 5-(2-hydroxypropan-2-yl)-3H-pyrimidin-4-one

To a stirred solution of methyl 4-oxo-3H-pyrimidine-5-carboxylate (3.00g, 19.46 mmol, 1.00 equiv) in THF (200 mL) was added MeMgBr (64 mL, 3Min 2-MeTHF, 194.65 mmol, 10.00 equiv) dropwise at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 1 h at 0° C. undernitrogen atmosphere. The reaction was quenched by the addition of sat.NH₄Cl (aq.) (100 mL) at 0° C. The resulting mixture was extracted withEtOAc (3×100 mL). The combined organic layers were washed with brine(100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. This resulted in5-(2-hydroxypropan-2-yl)-3H-pyrimidin-4-one (1.50 g, 49.99%) as a whitesolid. The crude product was used in the next step directly withoutfurther purification. LC-MS: (ES+H, m/z): [M+H]⁺=155.3.

Step 2: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of 5-(2-hydroxypropan-2-yl)-3H-pyrimidin-4-one (337mg, 2.19 mmol, 2.00 equiv) and2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(500 mg, 1.09 mmol, 1.00 equiv) in dioxane (20 mL) were added CuI (417mg, 2.19 mmol, 2.00 equiv), K₂CO₃ (302 mg, 2.19 mmol, 2.00 equiv) and(1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (311 mg, 2.19 mmol, 2.00equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred overnight at 80° C. under nitrogen atmosphere. Thereaction was monitored by LCMS. The mixture was allowed to cool down toroom temperature. The resulting mixture was filtered, the filter cakewas washed with EtOAc (3×20 mL). The resulting mixture was poured intowater (100 mL), extracted with EtOAc (100 mL). The combined organiclayers were washed with brine (200 mL), dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by Prep HPLC. This resulted in3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(130 mg, 22.41%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=530.2.

Step 3: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one&rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one)

The3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-6-oxopyrimidin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(260 mg) was separated by prep-chiral-HPLC to afford Example 10A (93.1mg, 99.2% purity, ee=100%) and Example 10B (73.9 mg, 99.6% purity,ee=100%) as a white solid.

Example 10A: LC-MS: (ES+H, m/z): [M+H]⁺=530.05. ¹H NMR (400 MHz,DMSO-d₆) δ 8.73 (s, 1H), 8.61 (s, 1H) 8.59 (d, 1H), 8.14 (s, 1H),8.09-8.06 (m, 1H), 7.79 (s, 1H), 6.81 (s, 1H), 5.49 (d, 2H), 5.22 (s,1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). ¹⁹F NMR(377 MHz, DMSO-d₆) δ −120.16, −120.18, −122.34, −122.36.

Example 10B: LC-MS: (ES+H, m/z): [M+H]⁺=530.05. ¹H NMR (400 MHz,DMSO-d₆) δ 8.73 (s, 1H), 8.61 (s, 1H) 8.59 (d, 1H), 8.14 (s, 1H),8.09-8.06 (m, 1H), 7.80 (s, 1H), 6.81 (s, 1H), 5.49 (d, 2H), 5.23 (s,1H), 2.10 (s, 3H), 2.00 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). ¹⁹F NMR(377 MHz, DMSO-d₆) δ−120.15, −120.17, −122.33, −122.35.

Example 11A, 11B

Step 1: Preparation of methyl2-(2-chloropyridin-3-yl)-2-methylpropanoate

To a stirred mixture of methyl 2-(2-chloropyridin-3-yl)acetate (5.00 g,26.93 mmol, 1.00 equiv) in THF (50 mL) was added LiHMDS (80.81 mL, 1 MinTHF, 80.81 mmol, 3.00 equiv) dropwise at −78° C. under nitrogenatmosphere. The resulting mixture was stirred for 30 min at −78° C.under nitrogen atmosphere. MeI (11.47 g, 80.81 mmol, 3.00 equiv) wasadded dropwise to the above solution at −78° C. under nitrogenatmosphere. The resulting mixture was stirred for 1 h at −78° C. undernitrogen atmosphere. Desired product could be detected by LCMS. Themixture was allowed to warm up room temperature. The reaction wasquenched with sat. NH₄Cl (aq.) (500 mL) at room temperature. Theresulting mixture was extracted with CH₂Cl₂ (3×500 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure to afford methyl2-(2-chloropyridin-3-yl)-2-methylpropanoate (5.7 g, crude) as acolorless oil. LC-MS: (ES+H, m/z): [M+H]⁺=214.1.

Step 2: Preparation of methyl2-(2-methoxypyridin-3-yl)-2-methylpropanoate

To a mixture of methyl 2-(2-chloropyridin-3-yl)-2-methylpropanoate (3.00g, 14.04 mmol, 1.00 equiv), Cs₂CO₃ (6.86 g, 21.06 mmol, 1.50 equiv),t-BuXPhos (0.36 g, 0.84 mmol, 0.06 equiv) and MeOH (20.00 mL, 493.97mmol, 35.18 equiv) in Toluene (20.00 mL) was added Pd(OAc)₂ (0.19 g,0.84 mmol, 0.06 equiv) at room temperature. The resulting mixture wasstirred overnight at 80° C. under nitrogen atmosphere. The mixture wasallowed to cool down to room temperature. The reaction was poured intowater (400 mL), extracted with EtOAc (3×400 mL). The combined organiclayers were dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure to afford methyl2-(2-methoxypyridin-3-yl)-2-methylpropanoate (2.40 g, crude) as a whitesolid. LC-MS: (ES+H, m/z): [M+H]⁺=210.2.

Step 3: Preparation of methyl2-methyl-2-(2-oxo-1H-pyridin-3-yl)propanoate

To a mixture of methyl 2-(2-methoxypyridin-3-yl)-2-methylpropanoate(2.00 g, 9.55 mmol, 1.00 equiv) in MeCN (50 mL) was added TMSI (7.65 g,38.23 mmol, 4.00 equiv) at room temperature. The resulting mixture wasstirred for 2 h at 50° C. under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to afford methyl2-methyl-2-(2-oxo-1H-pyridin-3-yl)propanoate (800 mg, 42.87%) as a whitesolid. LC-MS: (ES+H, m/z): [M+H]⁺=196.1. ¹H NMR (300 MHz, Chloroform-d)δ 7.44 (dd, 1H), 7.38 (dd, 1H), 6.33 (t, 1H), 3.66 (s, 3H), 1.52 (s,6H).

Step 4: Preparation of methyl2-(1-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2-oxo-[1,4′-bipyridin]-2′-yl}-2-oxopyridin-3-yl)-2-methylpropanoate

To a mixture of methyl 2-methyl-2-(2-oxo-1H-pyridin-3-yl)propanoate(0.85 g, 4.38 mmol, 1.00 equiv), K₂CO₃ (1.21 g, 8.76 mmol, 2.00 equiv),(1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.25 g, 1.75 mmol, 0.40equiv) and2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(2.00 g, 4.38 mmol, 1.00 equiv) in 1,4-dioxane (30.00 mL) was added CuI(0.17 g, 0.87 mmol, 0.20 equiv) at room temperature. The resultingmixture was stirred for 2 h at 80° C. under nitrogen atmosphere. Themixture was allowed to cool down to room temperature. The reaction waspoured into water (300 mL), extracted with EtOAc (3×300 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to affordmethyl2-(1-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2-oxo-[1,4′-bipyridin]-2′-yl}-2-oxopyridin-3-yl)-2-methylpropanoate(1.40 g, 55.99%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=571.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.14-8.05 (m, 1H),7.97-7.90 (m, 1H), 7.77 (s, 1H), 7.55-7.48 (m, 1H), 6.80 (s, 1H), 6.43(t, 1H), 5.54-5.44 (m, 2H), 3.49 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H),1.42 (s, 3H), 1.40 (s, 3H).

Step 5: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of methyl2-(1-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-2-oxo-[1,4′-bipyridin]-2′-yl}-2-oxopyridin-3-yl)-2-methylpropanoate(900 mg, 1.57 mmol, 1.00 equiv) in THF (12.00 mL) was added LiAlH₄ (0.63mL, 2.5 M in THF, 1.57 mmol, 1.00 equiv) dropwise at 0° C. undernitrogen atmosphere. The resulting mixture was stirred for 1 h at 0° C.under nitrogen atmosphere. The reaction was quenched with 15% sodiumhydroxide (aq.) at 0° C. The resulting mixture was filtered, thefiltrate was concentrated under reduced pressure. The crude product waspurified by Prep-HPLC to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(110 mg, 12.85%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=543.3.

Step 6: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The racemate3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(110 mg, 0.20 mmol) was purified by Prep-chiral-HPLC to affordrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 11A, 33.7 mg, ee=100.00%) as a white solid andrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 11B, 31.5 mg, ee=100.00%) as a white solid.

Example 11A: LC-MS: (ES+H, m/z): [M+H]⁺=543.3. ¹H NMR (300 MHz, DMSO-d₆)δ 8.68 (s, 1H), 8.61 (d, 1H), 8.15-8.05 (m, 1H), 7.86-7.80 (m, 1H), 7.75(s, 1H), 7.43-7.35 (m, 1H), 6.81 (s, 1H), 6.35 (t, 1H), 5.53-5.44 (m,2H), 4.49 (t, 1H), 3.74-3.56 (m, 2H), 2.08 (s, 3H), 2.02 (s, 3H), 1.23(s, 3H), 1.23 (s, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−120.15, −120.18,−122.35, −122.37.

Example 11B: LC-MS: (ES+H, m/z): [M+H]⁺=543.3. ¹H NMR (300 MHz, DMSO-d₆)δ 8.68 (s, 1H), 8.61 (d, 1H), 8.15-8.05 (m, 1H), 7.88-7.80 (m, 1H), 7.75(s, 1H), 7.44-7.34 (m, 1H), 6.81 (s, 1H), 6.35 (t, 1H), 5.53-5.44 (m,2H), 4.49 (t, 1H), 3.73-3.55 (m, 2H), 2.08 (s, 3H), 2.02 (s, 3H), 1.23(s, 3H), 1.23 (s, 3H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−120.15, −120.18,−122.35, −122.37.

Example 12A, 12B

Step 1: Preparation of 1-(2-methoxypyridin-3-yl)cyclobutan-1-ol

To a stirred solution of 3-iodo-2-methoxypyridine (5.00 g, 21.27 mmol,1.00 equiv) in Toluene (100.00 mL) was added i-PrMgCl (2.84 g, 27.65mmol, 1.30 equiv) dropwise at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 0.5 h at 0° C. under nitrogenatmosphere. To the above mixture was added cyclobutanone (2.24 g, 31.91mmol, 1.50 equiv) dropwise at 0° C. The resulting mixture was stirredfor additional 1 h at 0° C. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to afford 1-(2-methoxypyridin-3-yl)cyclobutan-1-ol (1.75g, 45.90%) as a yellow oil. LC-MS: (ES+H, m/z): [M+H]⁺=180.1. ¹H NMR(400 MHz, DMSO-d₆) δ 8.08-8.02 (m, 1H), 7.68-7.63 (m, 1H), 6.97-6.92 (m,1H), 5.20 (s, 1H), 3.88 (s, 3H), 2.61-2.48 (m, 2H), 2.22-2.13 (m, 2H),2.02-1.93 (m, 1H), 1.67-1.54 (m, 1H).

Step 2: Preparation of 3-(1-hydroxycyclobutyl)-1H-pyridin-2-one

To a mixture of 1-(2-methoxypyridin-3-yl)cyclobutan-1-ol (400 mg, 2.23mmol, 1.00 equiv) in DMF (10.00 mL) was added (ethylsulfanyl)sodium(1877 mg, 22.32 mmol, 10.00 equiv) at room temperature. The resultingmixture was stirred overnight at 100° C. under nitrogen atmosphere. Themixture was allowed to cool down to room temperature. The mixture wasneutralized to pH 7 with AcOH. The resulting mixture was filtered, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to afford3-(1-hydroxycyclobutyl)-1H-pyridin-2-one (200 mg, 54.25%) as a whitesolid. LC-MS: (ES+H, m/z): [M+H]⁺=166.1. ¹H NMR (400 MHz, DMSO-d₆) δ11.76 (s, 1H), 7.49 (dd, 1H), 7.32 (dd, 1H), 6.24 (t, 1H), 5.81-5.55 (m,1H), 2.48-2.41 (m, 2H), 2.13-2.02 (m, 2H), 1.93-1.81 (m, 1H), 1.65-1.53(m, 1H).

Step 3: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a mixture of 3-(1-hydroxycyclobutyl)-1H-pyridin-2-one (173 mg, 1.05mmol, 1.20 equiv), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (49 mg,0.35 mmol, 0.40 equiv), K₂CO₃ (242 mg, 1.75 mmol, 2.00 equiv) and2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(400 mg, 0.87 mmol, 1.00 equiv) in 1,4-dioxane (8.00 mL) was added CuI(33 mg, 0.17 mmol, 0.20 equiv) at room temperature. The resultingmixture was stirred for 2 h at 80° C. under nitrogen atmosphere. Thereaction was poured into water (150 mL), extracted with EtOAc (3×150mL). The combined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by reverse flash chromatography to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(280 mg, 59.09%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=541.1.

Step 3: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The racemate3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(280 mg, 0.51 mmol) was purified by Prep-chiral-HPLC to affordrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 12A, 100.8 mg, ee=100.00%) as a white solid andrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxycyclobutyl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 12B, 103.2 mg, ee=99.32%) as a white solid.

Example 12A: LC-MS: (ES+H, m/z): [M+H]⁺=541.2. ¹H NMR (400 MHz, DMSO-d₆)δ 8.70 (s, 1H), 8.60 (d, 1H), 8.15-8.05 (m, 1H), 7.95-7.90 (m, 1H), 7.84(s, 1H), 7.59 (dd, 1H), 6.81 (s, 1H), 6.44 (t 1H), 5.48 (s, 2H), 5.31(s, 1H), 2.64-2.54 (m, 2H), 2.13-2.09 (m, 1H), 2.08 (s, 3H), 2.07-2.03(m, 1H), 2.01 (s, 3H), 1.98-1.85 (m, 1H), 1.72-1.59 (m, 1H). ¹⁹F NMR(377 MHz, DMSO-d₆) δ−120.15, −120.17, −122.34, −122.36.

Example 12B: LC-MS: (ES+H, m/z): [M+H]⁺=541.2. ¹H NMR (400 MHz, DMSO-d₆)δ 8.70 (s, 1H), 8.60 (d, 1H), 8.14-8.06 (m, 1H), 7.95-7.89 (m, 1H), 7.84(s, 1H), 7.62-7.56 (m, 1H), 6.81 (s, 1H), 6.43 (t, 1H), 5.48 (s, 2H),5.31 (s, 1H), 2.64-2.54 (m, 2H), 2.12-2.09 (m, 1H), 2.08 (s, 3H),2.07-2.03 (m, 1H), 2.01 (s, 3H), 1.98-1.84 (m, 1H), 1.72-1.57 (m, 1H).¹⁹F NMR (377 MHz, DMSO-d₆) δ−120.16, −120.18, −122.34, −122.36.

Example 13A, Example 13B

Step 1: Preparation of 5-(2-hydroxypropan-2-yl)-1H-pyridin-2-one

To a stirred solution of methyl 6-oxo-1H-pyridine-3-carboxylate (1.00 g,6.53 mmol, 1.00 equiv) in THF (50 mL) was added MeMgBr (21.77 mL, 3 Min2-MeTHF, 65.30 mmol, 10.00 equiv) dropwise at −10° C. The resultingmixture was stirred for additional 1 h at room temperature. The reactionwas monitored by LCMS. The reaction was quenched by the addition of sat.NH₄Cl (aq.) (150 mL) at 0° C. The resulting mixture was extracted withEtOAc (4×300 mL). The combined organic layers were washed with brine(400 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure, to afford5-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (580 mg, 57.98%) as a whitesolid. LC-MS: (ES+H, m/z): [M+H]⁺=154.3.

Step 2: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of 5-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (537mg, 3.50 mmol, 2.00 equiv) and2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(800 mg, 1.75 mmol, 1.00 equiv) in 1,4-dioxane (6 mL) were added K₂CO₃(484 mg, 3.50 mmol, 2.00 equiv), CuI (667 mg, 3.50 mmol, 2.00 equiv) and(1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (498 mg, 3.50 mmol, 2.00equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 3 h at 80° C. under nitrogen atmosphere. Theresidue was diluted with H₂O (50 mL), and the mixture was extracted withEtOAc (2×100 mL). The combined organic phase was washed with brine (100mL), dried over Na₂SO₄. The crude product was purified by Prep-HPLC toafford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(130 mg, 14.03%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=529.05. ¹HNMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.60 (d, 1H), 8.13-8.05 (m, 1H),7.93 (d, 1H), 7.85 (s, 1H), 7.70-7.65 (m, 1H), 6.81 (s, 1H), 6.51 (d,1H), 5.50 (d, 2H), 5.18 (s, 1H), 2.09 (s, 3H), 2.02 (s, 3H), 1.41 (s,3H), 1.40 (s, 3H).

Step 3: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[5-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(130 mg, 0.233 mmol, 1.00 equiv) was separated by Prep-Chiral-HPLC toafford Example 13A (43.9 mg, 98.2% purity, ee=100%) as a white solid andExample 13B (33.6 mg, 98.3% purity, ee=100%) as a white solid.

Example 13A: LC-MS: (ES+H, m/z): [M+H]⁺=529.0. ¹H NMR (300 MHz, DMSO-d₆)δ 8.70 (s, 1H), 8.60 (d, 1H), 8.14-8.05 (m, 1H), 7.90 (d, 1H), 7.84 (s,1H), 7.70-7.64 (m, 1H), 6.81 (s, 1H), 6.50 (d, 1H), 5.49 (d, 2H), 5.17(s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−120.15, −120.17, −122.35, −122.38.

Example 13B: LC-MS: (ES+H, m/z): [M+H]⁺=529.0. ¹H NMR (300 MHz, DMSO-d₆)δ 8.70 (s, 1H), 8.60 (d, 1H), 8.14-8.05 (m, 1H), 7.90 (d, 1H), 7.84 (s,1H), 7.70-7.64 (m, 1H), 6.81 (s, 1H), 6.50 (d, 1H), 5.49 (d, 2H), 5.17(s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−120.15, −120.17, −122.35, −122.38.

Example 14A, 14B, 14C, 14D

Step 1: Preparation of 1-cyclopropyl-1-(2-methoxypyridin-3-yl)ethanol

To a stirred solution of 3-iodo-2-methoxypyridine (4.00 g, 17.02 mmol,1.00 equiv) in Toluene (100 mL) was added i-PrMgCl (11.06 mL, 2 M inTHF, 22.12 mmol, 1.30 equiv) dropwise at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 30 min at 0° C. undernitrogen atmosphere. To the above mixture was added cyclopropyl methylketone (2.15 g, 25.55 mmol, 1.50 equiv) dropwise over 20 min at 0° C.The resulting mixture was stirred for additional 1 h at 0° C. Thereaction was quenched with water at room temperature. The resultingmixture was extracted with EtOAc (3×200 mL). The combined organic layerswere washed with brine (2×100 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by reverse combi-flash chromatography to afford1-cyclopropyl-1-(2-methoxypyridin-3-yl)ethanol (751 mg, 22.83%) as ayellow oil. LC-MS: (ES+H, m/z): [M+H]⁺=194.1. ¹H NMR (300 MHz, DMSO-d₆)δ 8.02 (dd, 1H), 7.81 (dd, 1H), 6.95 (dd, 1H), 4.65 (s, 1H), 3.89 (s,3H), 1.66-1.56 (m, 1H), 1.54 (s, 3H), 0.58-0.41 (m, 1H), 0.35-0.12 (m,2H), 0.11-−0.04 (m, 1H).

Step 2: Preparation of product3-(1-cyclopropyl-1-hydroxyethyl)-1H-pyridin-2-one

A mixture of 1-cyclopropyl-1-(2-methoxypyridin-3-yl)ethanol (1.14 g,5.88 mmol, 1.00 equiv) and (ethylsulfanyl)sodium (4.95 g, 58.84 mmol,10.0 equiv) in DMF (20 mL) was stirred for 3 h at 100° C. under nitrogenatmosphere. The mixture was allowed to r.t. The resulting mixture wasdiluted with water (100 mL). The mixture was acidified to pH=4-5 withconc. HCl. The resulting mixture was extracted with CHCl₃:IPA=3:1 (3×100mL). The combined organic layers were concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford crude product3-(1-cyclopropyl-1-hydroxyethyl)-1H-pyridin-2-one (1.40 g) as a yellowoil. The crude product was used in the next step directly withoutfurther purification. LC-MS: (ES+H, m/z): [M+H]⁺=180.0. ¹H NMR (300 MHz,DMSO-d₆) δ 12.07-11.10 (m, 1H), 7.52 (dd, 1H), 7.29 (dd, 1H), 6.23 (t,1H), 5.56 (s, 1H), 1.54-1.46 (m, 1H), 1.44 (s, 3H), 0.50-0.30 (m, 1H),0.34-0.20 (m, 2H), 0.20-0.07 (m, 1H).

Step 3: Preparation of3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of 3-(1-cyclopropyl-1-hydroxyethyl)-1H-pyridin-2-one (1.30 g,7.25 mmol, 1.50 equiv),2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(2.21 g, 4.83 mmol, 1.00 equiv), K₂CO₃ (1.34 g, 9.67 mmol, 2.00 equiv),CuI (1.84 g, 9.67 mmol, 2.00 equiv) and(1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (1.38 g, 9.67 mmol, 2.00equiv) in 1,4-dioxane(10 ml) was stirred for 2 h at 80° C. The mixturewas allowed to cool down to r.t. The resulting mixture was diluted withwater (100 mL). The resulting mixture was extracted with EtOAc (3×150mL). The combined organic layers were washed with brine (150 mL), driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to afford3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(0.79 g, 29.40%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=555.0. ¹HNMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.15-8.03 (m, 1H),7.86 (dd, 1H), 7.79 (d, 1H), 7.70-7.61 (m, 1H), 6.80 (t, 1H), 6.43 (t,1H), 5.48 (d, 2H), 4.94 (d, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.72-1.62(m, 1H), 1.53 (d, 3H), 0.52-0.43 (m, 1H), 0.30-0.21 (m, 2H), 0.16-0.05(m, 1H).

Step 4: Preparation ofrel-3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one,rel-3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one,rel-3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The rac-mixture (570 mg) was separated by Prep-Chiral HPLC to afford amixture of Example 14A and Example 14B (270 mg),rel-3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 14C, 100.1 mg, 97.8% purity, de=100%) as an off-white solid,rel-3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 14D, 84.0 mg, 97.0% purity, de=98.2%).

The mixture of Example 14A and Example 14B (270 mg) was furtherseparated by Prep-Chiral HPLC to affordrel-3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 14A, 104.2 mg, 97.5% purity, de=100%) as an off-white solid andrel-3-chloro-2′-[3-(1-cyclopropyl-1-hydroxyethyl)-2-oxopyridin-1-yl]-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(Example 14B, 116.2 mg, 96.6% purity, de=100%)

Example 14A: LC-MS: (ES+H, m/z): [M+H]⁺=555.00. ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.16-8.04 (m, 1H), 7.87 (dd, 1H),7.80 (s, 1H), 7.66 (dd, 1H), 6.80 (s, 1H), 6.43 (t, 1H), 5.48 (d, 2H),4.96 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.73-1.61 (m, 1H), 1.53 (s,3H), 0.54-0.42 (m, 1H), 0.32-0.19 (m, 2H), 0.18-0.07 (m, 1H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−120.16, −120.18, −122.35, −122.37.

Example 14B: LC-MS: (ES+H, m/z): [M+H]⁺=555.00. ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.16-8.03 (m, 1H), 7.87 (dd, 1H),7.80 (s, 1H), 7.66 (dd, 1H), 6.80 (s, 1H), 6.43 (t, 1H), 5.48 (d, 2H),4.96 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.73-1.61 (m, 1H), 1.53 (s,3H), 0.53-0.43 (m, 1H), 0.32-0.20 (m, 2H), 0.18-0.06 (m, 1H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−120.16, −120.18, −122.35, −122.37.

Example 14C: LC-MS: (ES+H, m/z): [M+H]⁺=555.00. ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (s, 1H), 8.61 (d, 1H), 8.17-8.03 (m, 1H), 7.87 (dd, 1H),7.79 (s, 1H), 7.66 (dd, 1H), 6.81 (s, 1H), 6.43 (t, 1H), 5.48 (d, 2H),4.94 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.72-1.62 (m, 1H), 1.54 (s,3H), 0.54-0.44 (m, 1H), 0.30-0.21 (m, 2H), 0.16-0.05 (m, 1H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−120.16, −120.18, −122.35, −122.37.

Example 14D: LC-MS: (ES+H, m/z): [M+H]⁺=554.95. ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (s, 1H), 8.60 (d, 1H), 8.16-8.03 (m, 1H), 7.87 (dd, 1H),7.80 (s, 1H), 7.66 (dd, 1H), 6.80 (s, 1H), 6.43 (t, 1H), 5.48 (d, 2H),4.96 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.73-1.62 (m, 1H), 1.53 (s,3H), 0.52-0.42 (m, 1H), 0.31-0.21 (m, 2H), 0.17-0.07 (m, 1H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−120.16, −120.18, −122.35, −122.37.

Example 15A, 15B

Step 1: Preparation of methyl 2-methoxy-4-methylpyridine-3-carboxylate

To a stirred mixture of 3-bromo-2-methoxy-4-methylpyridine (2.00 g, 9.89mmol, 1.00 equiv) in MeOH (5 ml) was added Pd(dppf)Cl₂ (0.72 g, 0.99mmol, 0.10 equiv) and DIEA (3.84 g, 29.69 mmol, 3.00 equiv) at roomtemperature under carbon monoxide (20 atm) atmosphere. The resultingmixture was stirred for 24 h at 110° C. The reaction was poured intowater at room temperature. The aqueous layer was extracted with CH₂Cl₂(3×20 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous Na₂SO₄. The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to afford methyl 2-methoxy-4-methylpyridine-3-carboxylate(480 mg, 26.76%) as a yellow oil. LC-MS: (ES+H, m z): [M+H]⁺=181.9. ¹HNMR (300 MHz, DMSO-d₆) δ 8.12 (d, 1H), 6.97-6.92 (m, 1H), 3.85 (s, 3H),3.83 (s, 3H), 2.23 (s, 3H).

Step 2: Preparation of methyl 2-oxo-1H-pyridine-3-carboxylate

To a stirred mixture of methyl 2-methoxy-4-methylpyridine-3-carboxylate(710 mg, 3.91 mmol, 1.00 equiv) in MeCN was added TMSI (1.57 g, 7.83mmol, 2.00 equiv) dropwise at room temperature. The resulting mixturewas stirred for additional 4 h at 50° C. The reaction was poured intowater at room temperature. The aqueous layer was extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous Na₂SO₄. The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to afford methyl 2-oxo-1H-pyridine-3-carboxylate (540 mg,89.99%) as a yellow solid. LC-MS: (ES+H, m z): [M+H]⁺=168.1. ¹H NMR (400MHz, DMSO-d₆) δ 11.80 (s, 1H), 7.36 (d, 1H), 6.10 (d, 1H), 3.75 (s, 3H),2.10 (s, 3H).

Step 3: Preparation of3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyridin-2-one

To a stirred mixture of methyl 4-methyl-2-oxo-1H-pyridine-3-carboxylate(440 mg, 2.63 mmol, 1.00 equiv) in THF (5 mL) was addedbromo(methyl)magnesium 1 M in THF (26 mL, 26.32 mmol, 10.00 equiv)dropwise at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for additional 2 h at 80° C. The reaction was quenched with sat.NH₄Cl (aq.) at 0° C. The aqueous layer was extracted with EtOAc (3×20mL). The combined organic layers were washed with brine (50 mL), driedover anhydrous Na₂SO₄. The resulting mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to afford3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyridin-2-one (300 mg, 68.16%) as awhite solid. LC-MS: (ES+H, m/z): [M+H]⁺=168.3. ¹H NMR (300 MHz, DMSO-d₆)δ 11.68 (s, 1H), 7.42 (s, 1H), 7.20 (d, 1H), 6.08 (d, 1H), 2.31 (s, 3H),1.47 (s, 6H).

Step 4: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-4-methyl-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyridin-2-one (300 mg, 1.79 mmol,1.50 equiv) and(2E)-3-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}pent-2-enecarbonimidoylbromide (534 mg, 1.19 mmol, 1.00 equiv) in 1,4-dioxane(8 ml) were added(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (68 mg, 0.47 mmol, 0.40equiv), K₂CO₃ (330 mg, 2.39 mmol, 2.00 equiv) and CuI (45 mg, 0.23 mmol,0.20 equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for additional 2 h at 100° C. The reaction waspoured into water at room temperature. The aqueous layer was extractedwith EtOAc (4×30 mL). The resulting mixture was concentrated underreduced pressure. The crude product was purified by Prep-HPLC to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-4-methyl-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(380 mg, 58.51%) as a white solid. LC-MS: (ES+H, m z): [M+2+H]⁺=545.2.

Step 5: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-4-methyl-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-4-methyl-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The racemate (300 mg) was separated by Prep-Chiral-HPLC to affordExample 15A (130.3 mg, 97.7% purity, ee=100%) as a white solid andExample 15B (130.0 mg, 98.3% purity, ee=100%) as a white solid.

Example 15A: LC-MS: (ES+H, m/z): [M+H]⁺=543.0. ¹H NMR(400 MHz, DMSO-d₆)δ 8.66 (s, 1H), 8.60 (d, 1H), 8.11-8.06 (m, 1H), 7.77-7.71 (m, 2H), 6.80(s, 1H), 6.21 (d, 1H), 5.89 (s, 1H), 5.48 (d, 2H), 2.45 (s, 3H), 2.07(s, 3H), 1.99 (s, 3H), 1.54 (s, 3H), 1.53 (s, 3H). ¹⁹F NMR (377 MHz,DMSO-d₆) δ −120.16, −120.18, −122.36, −122.38.

Example 15B: LC-MS: (ES+H, m/z): [M+H]⁺=543.1. ¹H NMR(400 MHz, DMSO-d₆)δ 8.66 (s, 1H), 8.60 (d, 1H), 8.11-8.06 (m, 1H), 7.77-7.71 (m, 2H), 6.80(s, 1H), 6.21 (d, 1H), 5.89 (s, 1H), 5.48 (d, 2H), 2.45 (s, 3H), 2.07(s, 3H), 1.99 (s, 3H), 1.54 (s, 3H), 1.53 (s, 3H). ¹⁹F NMR (377 MHz,DMSO-d₆) δ −120.16, −120.18, −122.35, −122.37.

Example 16A, 16B

Step 1: Preparation of5′-bromo-4-hydroxy-2′,6-dimethyl-[1,3′-bipyridin]-2-one

A solution of 5-bromo-2-methylpyridin-3-amine (10.00 g, 53.46 mmol, 1.00equiv) and 2,2-dimethyl-6-(2-oxopropyl)-1,3-dioxin-4-one (19.70 g,106.92 mmol, 2.00 equiv) in 1,4-dioxane (100 mL) was stirred for 2 h at80° C. under nitrogen atmosphere. To the above mixture was added H₂SO₄(3.99 mL, 74.85 mmol, 1.40 equiv) dropwise at 0° C. The resultingmixture was stirred for another 2 h at 80° C. under nitrogen atmosphere.The mixture was allowed to r.t. The resulting mixture was concentratedunder reduced pressure. The residue was dissolved in water (50 mL) andEt₂O (100 mL). The precipitated solids were collected by filtration andwashed with Et₂O (3×10 mL), to afford5′-bromo-4-hydroxy-2′,6-dimethyl-[1,3′-bipyridin]-2-one (15.00 g,95.06%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=294.9.

Step 2: Preparation of5′-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′,6-dimethyl-[1,3′-bipyridin]-2-one

To a stirred mixture of5′-bromo-4-hydroxy-2′,6-dimethyl-[1,3′-bipyridin]-2-one (3.00 g, 10.16mmol, 1.00 equiv) and 2-(chloromethyl)-3,5-difluoropyridine (3.32 g,20.33 mmol, 2.00 equiv) in DMF (70 mL) were added 18-Crown-6 (0.81 g,3.06 mmol, 0.30 equiv) and K₂CO₃ (7.02 g, 50.79 mmol, 5.00 equiv) atr.t. The result mixture was stirred for 3 h at 60° C. under nitrogenatmosphere. The mixture was allowed to cool down to room temperature.The resulting mixture was filtered, the filter cake was washed with DCM(3×50 mL). The filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to afford5′-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′,6-dimethyl-[1,3′-bipyridin]-2-one(1.90 g, 44.27%) as alight yellow solid. LC-MS: (ES+H, m/z):[M+H]⁺=422.0.

Step 3: Preparation of 5′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′,6-dimethyl-[1,3′-bipyridin]-2-one

To a stirred mixture of5′-bromo-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′,6-dimethyl-[1,3′-bipyridin]-2-one(1.70 g, 4.02 mmol, 1.00 equiv) and NCS (537 mg, 4.02 mmol, 1.00 equiv)in i-PrOH (9 mL) was added 2,2-dichloroacetic acid (51 mg, 0.40 mmol,0.10 equiv) dropwise at room temperature. The resulting mixture wasstirred for 2 h at 60° C. under nitrogen atmosphere. The mixture wasallowed to cool down to room temperature. The precipitated solids werecollected by filtration and washed with hexane (3×10 mL). This resultedin 5′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′,6-dimethyl-[1,3′-bipyridin]-2-one (880 mg, 47.86%) as awhite solid. LC-MS: (ES+H, m/z): [M+H]⁺=457.9.

Step 4: Preparation of 5′-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6′-methyl-[1,3′-bipyridin]-2-one

To a stirred mixture of 5′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′,6-dimethyl-[1,3′-bipyridin]-2-one (700 mg, 1.53 mmol, 1.00equiv) and 3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (469 mg, 3.06 mmol,2.00 equiv) in 1,4-dioxane (14 mL) were added CuI (58 mg, 0.30 mmol,0.20 equiv), K₂CO₃ (423 mg, 3.06 mmol, 2.00 equiv) andN1,N2-dimethylcyclohexane-1,2-diamine (87 mg, 0.61 mmol, 0.40 equiv).The resulting mixture was stirred for 3 h at 90° C. under nitrogenatmosphere. The mixture was allowed to cool down to room temperature.The resulting mixture was filtered, the filter cake was washed withEtOAc (3×15 mL). The filtrate was poured into water (60 mL) andextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (80 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by PREP HPLC to afford5′-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6′-methyl-[1,3′-bipyridin]-2-one(303 mg, 37.3%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=529.3.

Step 5: Preparation ofrel-5′-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6′-methyl-[1,3′-bipyridin]-2-one&rel-5′-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6′-methyl-[1,3′-bipyridin]-2-one

5′-{3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-6′-methyl-[1,3′-bipyridin]-2-one(290 mg) was separated by Prep-Chiral-HPLC to afford Example 16A (90.1mg, 97.1% purity, ee=100.0%) and Example 16B (66.3 mg, 98.6% purity,ee=100.0%) as a white solid.

Example 16A: LC-MS: (ES+H, m/z): [M+H]⁺=529.0. ¹H NMR (300 MHz, DMSO-d₆)δ 8.67 (d, 1H), 8.60 (d, 1H), 8.15-8.05 (m, 1H), 8.02 (d, 1H), 7.76-7.65(m, 2H), 6.80 (s, 1H), 6.42 (t, 1H), 5.49 (d, 2H), 5.25 (s, 1H), 2.26(s, 3H), 2.01 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−120.13, −120.16, −122.34, −122.37.

Example 16B: LC-MS: (ES+H, m/z): [M+H]⁺=529.0. ¹H NMR (300 MHz, DMSO-d₆)δ 8.67 (d, 1H), 8.60 (d, 1H), 8.16-8.05 (m, 1H), 8.02 (d, 1H), 7.77-7.66(m, 2H), 6.81 (s, 1H), 6.42 (t, 1H), 5.49 (d, 2H), 5.26 (s, 1H), 2.26(s, 3H), 2.01 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −120.13, −120.15, −122.33, −122.36.

Example 17A, 17B

Step 1: Preparation of 3-(prop-1-en-2-yl)-1H-pyridin-2-one

To a stirred mixture of 3-bromo-TH-pyridin-2-one (6.00 g, 34.48 mmol,1.00 equiv) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (23.18 g,137.93 mmol, 4.00 equiv) in 1,4-dioxane (60 mL) and H₂O (10 mL) wereadded K₂CO₃ (9.53 g, 68.96 mmol, 2.00 equiv), Pd(dppf)Cl₂ (3.78 g, 5.17mmol, 0.15 equiv) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at 100° C. The reaction mixturewas poured into water and the aqueous layer was extracted with EtOAc(3×100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to afford3-(prop-1-en-2-yl)-1H-pyridin-2-one (1.2 g, 11.1%, 50% purity) as ayellow solid. LC-MS: (ES+H, m/z): [M+H]⁺=135.9.

Step 2: Preparation of 3-(prop-1-en-2-yl)-1H-pyridin-2-one

To a stirred mixture of 3-(prop-1-en-2-yl)-1H-pyridin-2-one (1.00 g) inDCM (10 ml) was added TFA (10 mL) and SiH(Et)₃ (5 mL) at roomtemperature under nitrogen atmosphere. The resulting mixture was stirredfor 24 h at r.t. under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure to afford3-(prop-1-en-2-yl)-1H-pyridin-2-one (2.00 g, crude). The crude productwas used in the next step directly without further purification. LC-MS:(ES+H, m/z): [M+H]⁺=138.1.

Step 3: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-(3-isopropyl-2-oxopyridin-1-yl)-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of 3-isopropyl-1H-pyridin-2-one (600 mg, 4.38 mmol,2.00 equiv) and2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(1.00 g, 2.19 mmol, 1.00 equiv) in 1,4-dioxane (6 mL) were added(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (624 mg, 4.38 mmol, 2.00equiv), CuI (835 mg, 4.38 mmol, 2.00 equiv) and K₂CO₃ (597 mg, 4.38mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at 80° C. The mixture was allowedto cool down to room temperature. The reaction mixture was poured intowater (30 mL) aqueous layer was extracted with EtOAc (3×50 mL), driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to afford crude product, which was further purified byPrep-HPLC to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-(3-isopropyl-2-oxopyridin-1-yl)-5′,6-dimethyl-[1,4′-bipyridin]-2-one(220 mg, 69.4%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=513.2.

Step 4: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-(3-isopropyl-2-oxopyridin-1-yl)-5′,6-dimethyl-[1,4′-bipyridin]-2-one&rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-(3-isopropyl-2-oxopyridin-1-yl)-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The racemate (180 mg) was separated by prep-chiral-HPLC to affordExample 17A (63.2 mg, 99.7% purity, ee=100%) and Example 17B (62.0 mg,96.3% purity, ee=100%) as a white solid.

Example 17A: LC-MS: (ES+H, m/z): [M+H]⁺=513.1. ¹H NMR (300 MHz, DMSO-d₆)δ 8.68 (s, 1H), 8.60 (d, 1H), 8.12-8.06 (m, 1H), 7.84-7.81 (m, 2H),7.38-7.36 (m, 1H), 6.81 (s, 1H), 6.40-6.35 (m, 1H), 5.49 (d, 2H),3.09-3.00 (m, 1H), 2.07 (s, 3H), 2.01 (s, 3H), 1.16-1.13 (m, 6H). ¹⁹FNMR (282 MHz, DMSO-d₆) δ−120.16, −120.18, −122.36, −122.38.

Example 17B: LC-MS: (ES+H, m/z): [M+H]⁺=512.95. ¹H NMR (300 MHz,DMSO-d₆) δ 8.68 (s, 1H), 8.60 (d, 1H), 8.13-8.06 (m, 1H), 7.84-7.81 (m,2H), 7.38-7.36 (m, 1H), 6.80 (s, 1H), 6.40-6.35 (m, 1H), 5.49 (d, 2H),3.09-3.00 (m, 1H), 2.07 (s, 3H), 2.01 (s, 3H), 1.16-1.13 (m, 6H). ¹⁹FNMR (282 MHz, DMSO-d₆) δ−120.16, −120.18, −122.36, −122.38.

Example 18A, 18B

Step 1: Preparation of3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione

To a stirred solution of2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(25.00 g, 54.50 mmol, 1.00 equiv),(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (3.10 g, 21.79 mmol, 0.40equiv), K₂CO₃(15.07 g, 109.00 mmol, 2.00 equiv) and CuI (2.08 g, 10.90mmol, 0.20 equiv) in dioxane (210 mL) was added3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (26.72 g, 174.43 mmol, 2.00equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 3 h at 80° C. under nitrogen atmosphere. Themixture was allowed to cool to room temperature. The resulting mixturewas filtered, the filter cake was washed with ethyl acetate (3×100 mL).The filtrate was diluted with ethyl acetate (2 L) and washed with water(10% NH₃, 3×1 L). The organic layer was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford crude product (23.88 g) as a light yellow solid, which wasfurther purified by recrystallization from ACN, the materials weredissolved in ACN at 80° C., then cooled to r.t. for 2 h, and kept at 4°C. overnight. The precipitated solids were collected by filtration andwashed with cold ACN (4×20 mL), to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(18.21 g, 62.8% yield, 97.2% purity) as a white solid. LC-MS: (ES+H,m/z): [M+H]⁺=531.1. ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.60 (d,1H), 8.09 (ddd, 1H), 7.86 (dd, 1H), 7.80 (s, 1H), 7.70 (dd, 1H), 6.81(d, 1H), 6.43 (t 1H), 5.24 (s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.48 (s,3H), 1.47 (s, 3H).

Step 2: Preparation ofrel-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione(Example 18A)

The racemate (65.00 g) was separated by Prep-Chiral-SFC. The purefraction was concentrated under reduced pressure to afford the solid,which was re-dissolved in ACN and then concentrated to dryness. Theproduct was suspended in water (120 mL) at 50° C. for 30 min and thenallowed to r.t. and kept at 4° C. for 20 min, the precipitated solid wascollected to affordrel-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione(Example 18A: 29.42 g, 98.4% purity, 97.8% deuterium purity, ee=100%) asa white solid and Example 18B (˜30.40 g).

30 g of the isomer 2 (Example 18B) in dioxane (200 mL) was heated for 24h at 100° C., the resulting mixture was concentrated to afford theracemate (˜30 g), which was combined with another 6 g from previousmother liquor and then further separated by Prep-Chiral-SFC. The purefraction was concentrated under reduced pressure to afford the solid,which was re-dissolved in ACN and then concentrated to dryness, toaffordrel-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione(Example 18A: 15.10 g, 99.2% purity, 97.8% deuterium purity) as a whitesolid and Example 18B (˜15.40 g, white solid).

The 2 batches of Example 18A was combined (44.52 g) and then suspendedin a co-solvent of IPA and water (440 mL, V_(IPA)/V_(H2O)=1:6), theslurry was stirred at room temperature for 30 min an then the seed wasadded, the resulting mixture was stirred for additional 48 hours beforestorage at 4° C. for 30 min, the precipitated solid was collected anddried to afford rel-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione(Example 18A: 41.62 g 99.3% purity, 97.9% deuterium purity, ee=100%).

Example 18A: LC-MS: (ES+H, m/z): [M+H]⁺=531.15. ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (s, 1H), 8.61 (d, 1H), 8.16-8.03 (m, 1H), 7.86 (dd, 2.1Hz, 1H), 7.80 (s, 1H), 7.70 (dd, 1H), 6.81 (s, 1H), 6.43 (t, 1H), 5.24(s, 1H), 2.08 (s, 3H), 2.01 (s, 3H), 1.47 (d, 6H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ −120.22, −120.24, −122.28, −122.31.

Example 19A, 19B

Step 1: Preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(25.00 g, 54.50 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (25.21 g, 163.51 mmol, 3.00equiv), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (1.55 g, 10.90mmol, 0.20 equiv), K₂CO₃ (15.07 g, 109.00 mmol, 2.00 equiv) and CuI(1.04 g, 5.45 mmol, 0.10 equiv) in dioxane (250 ml) was stirred for 2 hat 80° C. under nitrogen atmosphere. The mixture was allowed to cooldown to room temperature. The resulting mixture was diluted with EtOAc(500 mL). The resulting mixture was washed with water (10% NH₃.H₂O,5×300 mL). The combined organic layers were washed with brine (500 mL),dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, the pure fraction was concentrated underreduced pressure to afford crude product (21.5 g) as a yellow solid. Thecrude product was recrystallized from ACN (150 mL) to afford3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(16.50 g, 56.91%) as alight yellow solid. LC-MS: (ES+H, m/z):[M+H]⁺=532.3.

Step 2: Preparation ofrel-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one&rel-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-6-methyl-2H-[1,4′-bipyridin]-2-one

The racemate (80.00 g) was separated by Prep-Chiral-SFC. The purefraction was concentrated under reduced pressure to afford the crudeproduct and Example 19B (˜35.00 g). The crude product was re-dissolvedin ACN and then concentrated to dryness. The solid was suspended inwater (150 mL), stirred for 30 min at 50° C. and then allowed to r.t.,the precipitated solid was collected and dried to afford Example 19A(33.60 g, 98.2% purity, 98.1% deuterium purity, ee=99.8%) as a lightyellow solid.

35 g of the isomer 2 (Example 19B) in dioxane (200 mL) was heated for 24h at 100° C., the resulting mixture was concentrated to afford theracemate (˜35 g) and then further separated by Prep-Chiral-SFC. The purefraction was concentrated under reduced pressure to afford the solid,which was re-dissolved in ACN and then concentrated to dryness, toaffordrel-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione(Example 19A: 16.1 g, 98.0% purity, 97.7% deuterium purity, ee=100.0%)as a white solid and Example 19B (˜15.20 g, yellow solid).

The 2 batches of Example 19A was combined (49.51 g). The product wasre-dissolved in ACN and then concentrated to dryness. The product wassuspended in water (150 mL), stirred for 30 min at 50° C. and thenallowed to r.t., the precipitated solid was collected to afford (Example19A: 98.0% purity, 97.7% deuterium purity, ee=100.0%) as a light yellowsolid.

Example 19A: LC-MS: (ES+H, m/z): [M+H]⁺=532.25. ¹H NMR (400 MHz,DMSO-d₆) δ 8.75 (s, 1H), 8.60 (d, 1H), 8.13-8.07 (m, 1H), 8.00 (d, 1H),7.94 (s, 1H), 7.48 (d, 1H), 6.82 (d, 1H), 5.13 (s, 1H), 2.11 (s, 3H),2.01 (s, 3H), 1.51 (s, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−120.25,−120.27, −122.32, −122.34.

Example 19B: LC-MS: (ES+H, m/z): [M+H]⁺=532.3. ¹H NMR (400 MHz, DMSO-d6)δ 8.75 (s, 1H), 8.60 (d, 1H), 8.13-8.07 (m, 1H), 8.00 (d, 1H), 7.94 (s,1H), 7.48 (d, 1H), 6.82 (d, 1H), 5.13 (s, 1H), 2.11 (s, 3H), 2.01 (s,3H), 1.51 (s, 6H). 19F NMR (377 MHz, DMSO-d6) δ−120.25, −120.27,−122.32, −122.34.

Example 20A, 20B

Step 1: Preparation of3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(15.00 g, 31.57 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (9.73 g, 63.14 mmol, 2.00equiv), K₂CO₃ (8.73 g, 63.14 mmol, 2.00 equiv), CuI (1.20 g, 6.31 mmol,0.20 equiv) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (1.80 g,12.62 mmol, 0.40 equiv) in dioxane (120 mL) was stirred for 2 h at 80°C. under nitrogen atmosphere. The mixture was allowed to roomtemperature. The resulting mixture was diluted with ethyl acetate (1500mL) and washed with water (10% NH₃, 3×500 mL). The organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to afford crude product (13 g) as a whitesolid. The crude product was recrystallized from DCM (20 mL) and ACN (40mL) to afford3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(9.26 g, 53.49%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=548.2. ¹HNMR (400 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.61 (dd, 1H), 8.24 (dd, 1H),8.00 (d, 1H), 7.94 (s, 1H), 7.47 (d, 1H), 6.79 (d, 1H), 5.12 (s, 1H),2.10 (s, 3H), 2.00 (s, 3H), 1.50 (s, 6H).

Step 2: Preparation ofrel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

The racemate (9.20 g) was separated by Prep-SFC to affordrel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Example 20A: 3.47 g, 98.6% purity, 96.5% deuterium purity, ee=100%) asa white solid andrel-3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Example 20B: 3.55 g, 97.2% purity, 96.3% deuterium purity, ee=100%) asa white solid.

Example 20A: LC-MS: (ES+H, m/z): [M+H]⁺=548.1. ¹H NMR (400 MHz, DMSO-d₆)δ 8.74 (s, 1H), 8.61 (dd, 1H), 8.24 (dd, 1H), 8.00 (d, 1H), 7.94 (s,1H), 7.47 (d, 1H), 6.79 (s, 1H), 5.12 (s, 1H), 2.10 (s, 3H), 2.00 (s,3H), 1.51 (s, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−121.68.

Example 20B: LC-MS: (ES+H, m/z): [M+H]⁺=548.0. ¹H NMR (400 MHz, DMSO-d₆)δ 8.74 (s, 1H), 8.61 (dd, 1H), 8.24 (dd, 1H), 8.00 (d, 1H), 7.95 (s,1H), 7.47 (d, 1H), 6.79 (s, 1H), 5.13 (s, 1H), 2.10 (s, 3H), 2.00 (s,3H), 1.51 (s, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−121.68.

Example 21A, 21B

Step 1: Preparation of3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(1.00 g, 2.10 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (0.64 g, 4.21 mmol, 2.00equiv), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.20 g, 1.05mmol, 1.00 equiv), K₂CO₃ (0.58 g, 4.21 mmol, 2.00 equiv) and CuI (0.30g, 2.10 mmol, 0.50 equiv) in dioxane (10 mL) was stirred for 2 h at 80°C. under nitrogen atmosphere. The mixture was allowed to cool down toroom temperature. The resulting mixture was diluted with EtOAc (20 mL).The resulting mixture was washed with water (10% NH₃.H₂O, 3×20 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The crude product was purified by Prep-HPLC to afford3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(680 mg, 58.6%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=547.1.

Step 2: Preparation ofrel-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one&rel-3-chloro-4-[(5-chloro-3-fluoropyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The racemate (680 mg) was separated by prep-SFC to afford Example 21A(103.8 mg, 98.1% purity, 97.6% deuterium purity, ee=100.0%) and Example21B (75.4 mg, 95.3% purity, 97.0% deuterium purity, ee=100.0%) as awhite solid.

Example 21A: LC-MS: (ES+H, m/z): [M+H]⁺=547.2. ¹H NMR (300 MHz, DMSO-d₆)δ 8.69 (s, 1H), 8.61 (s, 1H), 8.30-8.20 (m, 1H), 7.91-7.82 (m, 1H), 7.79(s, 1H), 7.75-7.66 (m, 1H), 6.78 (s, 1H), 6.43 (t, 1H), 5.24 (s, 1H),2.08 (s, 3H), 2.00 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). ¹⁹F NMR (282MHz, DMSO-d₆) δ−121.66.

Example 21B: LC-MS: (ES+H, m/z): [M+H]⁺=547.3. ¹H NMR (300 MHz, DMSO-d₆)δ 8.69 (s, 1H), 8.61 (d, 1H), 8.32-8.19 (m, 1H), 7.91-7.82 (m, 1H), 7.79(s, 1H), 7.75-7.66 (m, 1H), 6.78 (s, 1H), 6.43 (t, 1H), 5.23 (s, 1H),2.08 (s, 3H), 2.00 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). ¹⁹F NMR (282MHz, DMSO-d₆) δ−121.67.

Example 22A, 22B

Step 1: Preparation of3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(16.00 g, 33.67 mmol, 1 equiv),3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (454.26 mg, 2.94 mmol, 2.00equiv), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (83.83 mg, 0.58mmol, 0.40 equiv), CuI (0.80 g, 4.20 mmol, 0.20 equiv) and K₂CO₃ (407.22mg, 2.94 mmol, 2.00 equiv) in 1,4-dioxane (100 ml) was stirred for 2 hat 80° C. under nitrogen atmosphere. The mixture was allowed to roomtemperature. The resulting mixture was diluted with ethyl acetate (1000mL) and washed with water (10% NH₃, 3×500 mL). The organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to afford crude product (9.8 g). The crudeproduct was recrystallized from ACN (50 ml) to afford3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(8.4 g, 43.67%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=548.0. ¹HNMR (400 MHz, DMSO-d₆) δ8.75 (s, 1H), 8.68 (d, 1H), 8.25 (dd, 1H), 8.00(d, 1H), 7.95 (s, 1H), 7.47 (d, 1H), 6.78 (d, 1H), 5.13 (s, 1H), 2.10(s, 3H), 2.00 (s, 3H), 1.51 (s, 6H).

Step 2: Preparation ofrel-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy-d2)-2′-(3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1(2H)-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

The racemate (8.40 g) was separated by Prep-Chiral-SFC to afford Example22A (3.23 g, 98.2% purity, ee=100%, [a]²⁵ _(D) (c=1.075, MeOH): −136.93)as a white solid and Example 22B (3.13 g, 95.0% purity, ee=100%, [a]²⁵_(D) (c=1.075, MeOH): +127.53) as a white solid.

Example 22A: LC-MS: (ES+H, m/z): [M+H]⁺=548.2. ¹H NMR (300 MHz, DMSO-d₆)δ 8.75 (s, 1H), 8.68 (d, 1H), 8.25 (dd, 1H), 8.00 (d, 1H), 7.95 (s, 1H),7.48 (d, 1H), 6.79 (s, 1H), 5.13 (s, 1H), 2.11 (s, 3H), 2.00 (s, 3H),1.51 (s, 6H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.18, −124.20.

Example 22B: LC-MS: (ES+H, m/z): [M+H]⁺=548.2. ¹H NMR (300 MHz, DMSO-d₆)δ 8.75 (s, 1H), 8.68 (d, 1H), 8.25 (dd, 1H), 8.00 (d, 1H), 7.96 (s, 1H),7.48 (d, 1H), 6.79 (s, 1H), 5.13 (s, 1H), 2.11 (s, 3H), 2.00 (s, 3H),1.51 (s, 6H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.18, −124.20.

Example 23A, 23B

Step 1: Preparation of4′-{3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(600 mg, 1.26 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (386 mg, 2.52 mmol, 2.00equiv), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (71 mg, 0.50 mmol,0.40 equiv), K₂CO₃ (349 mg, 2.52 mmol, 2.00 equiv) and CuI (48 mg, 0.25mmol, 0.20 equiv) in dioxane (6 ml) was stirred for 2 h at 80° C. undernitrogen atmosphere. The mixture was allowed to cool down to roomtemperature. The resulting mixture was diluted with EtOAc (20 mL). Theresulting mixture was washed with water (10% NH₃.H₂O, 3×20 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The crude product (550 mg) was purified by Prep-HPLCto afford4′-{3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one(550 mg, 79.57%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=547.0.

Step 2: Preparation ofrel-4′-{3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one&rel-4′-{3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)(2H2)methoxy]-6-methyl-2-oxopyridin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one

The racemate (500 mg) was separated by prep-SFC to afford Example 23A(192.8 mg, 98.4% purity, 95.9% deuterium purity, ee=100.0%) as a whitesolid and Example 23B (201.8 mg, 98.4% purity, 96.0% deuterium purity,ee=100.0%) as a white solid.

Example 23A: LC-MS: (ES+H, m/z): [M+H]⁺=547.00. ¹H NMR (400 MHz,DMSO-d₆) δ 8.70-8.64 (m, 2H), 8.25 (dd, 1H), 7.86 (dd, 1H), 7.79 (s,1H), 7.70 (dd, 1H), 6.77 (s, 1H), 6.42 (t, 1H), 5.22 (s, 1H), 2.08 (s,3H), 2.00 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−124.16.

Example 23B: LC-MS: (ES+H, m/z): [M+H]⁺=547.05. ¹H NMR (400 MHz,DMSO-d₆) δ 8.71-8.65 (m, 2H), 8.25 (dd, 1H), 7.86 (dd, 1H), 7.79 (s,1H), 7.70 (dd, 1H), 6.77 (s, 1H), 6.42 (t, 1H), 5.23 (s, 1H), 2.08 (s,3H), 2.00 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−124.16.

Example 24A, 24B

Step 1: Preparation of2′-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of 2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one(1.32 g, 4.40 mmol, 1.00 equiv),3-chloro-2-(chloromethyl)-5-fluoropyridine (2.43 g, 13.21 mmol, 3.00equiv), 18-crown-6 (349 mg, 1.32 mmol, 0.30 equiv) and K₂CO₃ (3.71 g,26.43 mmol, 6.00 equiv) in DMF (8 mL) was stirred for 1 h at 60° C.under nitrogen atmosphere. The resulting mixture was diluted with ethylacetate (300 mL), washed with 3×100 mL of H₂O. The organic layers wereconcentrated under reduced pressure and purified by silica gel columnchromatography to afford2′-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(1.30 g, 66.2%) as a yellow oil. LC-MS: (ES+H, m/z): [M+H]⁺=440.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.68-8.65 (m, 1H), 8.48 (s, 1H), 8.25-8.20 (m,1H), 7.74 (s, 1H), 6.16-6.12 (m, 1H), 6.02 (d, 1H), 5.26 (s, 2H), 1.97(s, 3H), 1.86 (s, 3H).

Step 2: Preparation of2′-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

2′-bromo-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(1.10 g, 2.50 mmol, 1.00 equiv), NCS (401 mg, 3.01 mmol, 1.20 equiv),2,2-dichloroacetic acid (323 mg, 2.50 mmol, 1.00 equiv) was added to theIPA (5 mL) at room temperature. The resulting mixture was stirred for 2h at 60° C. under nitrogen atmosphere. The mixture was allowed to r.t.The resulting mixture was filtered, the filter cake was washed with IPA(3×5 mL). The filtrate was concentrated under reduced pressure. Thisresulted in2′-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(810 mg, 68.2%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=474.0. ¹HNMR (400 MHz, DMSO-d₆) δ 8.67 (d, 1H), 8.52 (s, 1H), 8.25 (dd, 1H), 7.81(s, 1H), 6.76 (s, 1H), 5.48 (d, 2H), 1.96 (s, 3H), 1.94 (s, 3H).

Step 3: Preparation of3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(725 mg, 1.53 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (708 mg, 4.59 mmol, 3.00equiv), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (87 mg, 0.61 mmol,0.40 equiv), CuI (58 mg, 0.30 mmol, 0.20 equiv), K₂CO₃ (423 mg, 3.06mmol, 2.00 equiv) in dioxane (5 mL) was stirred for 3 h at 80° C. undernitrogen atmosphere. The resulting mixture was diluted with ethylacetate (150 mL), washed with 3×50 mL of 10% NH₃.H₂O. The organic layerswere concentrated under reduced pressure and the residue was purified bysilica gel column chromatography to afford crude product, which wasfurther purified by PREP-HPLC. This resulted in3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(140 mg, 16.7%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=546.2.

Step 4: Preparation ofrel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one&rel-3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

3-chloro-4-[(3-chloro-5-fluoropyridin-2-yl)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(140 mg) was separated by prep-chiral-HPLC to afford Example 24A (57.6mg, 99.7% purity, ee=100.0%) and Example 24B (42.6 mg, 99.6% purity,ee=100%) as a white solid.

Example 24A: LC-MS: (ES+H, m/z): [M+H]⁺=546.00. ¹H NMR (300 MHz,DMSO-d₆) δ 8.75 (s, 1H), 8.68 (d, 1H), 8.26 (dd, 1H), 8.00 (d, 1H), 7.95(s, 1H), 7.48 (d, 1H), 6.79 (s, 1H), 5.51 (s, 2H), 5.13 (s, 1H), 2.10(s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−124.24.

Example 24B: LC-MS: (ES+H, m/z): [M+H]⁺=546.00. ¹H NMR (300 MHz,DMSO-d₆) δ 8.75 (s, 1H), 8.68 (d, 1H), 8.26 (dd, 1H), 8.00 (d, 1H), 7.95(s, 1H), 7.48 (d, 1H), 6.79 (s, 1H), 5.51 (s, 2H), 5.13 (s, 1H), 2.10(s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−124.24.

Example 25A, 25B

Step 1: Preparation of 2-chloro-4-iodo-5-methylpyridine

To a stirred mixture of 2-chloro-5-methylpyridin-4-amine (20 g, 140.26mmol, 1.00 equiv) and triiodomethane (82.84 g, 210.39 mmol, 1.5 equiv)in THF (200 mL) was added tBuONO (21.7 g, 210.39 mmol, 1.5 equiv)dropwise at 0° C. under nitrogen atmosphere. The mixture was stirred for1 h at room temperature. And the mixture was stirred for additional 3 hat 50° C. under nitrogen atmosphere. The mixture was allowed to cooldown to r.t. The resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford 2-chloro-4-iodo-5-methylpyridine (29 g, 81.57%) as a yellowsolid. LC-MS: (ES+H, m/z): [M+H]⁺=253.9. ¹H NMR (400 MHz, DMSO-d₆) δ8.26 (s, 1H), 8.01 (s, 1H), 2.33 (s, 3H).

Step 2: Preparation of N-(2-chloro-5-methylpyridin-4-yl)acetimidamide

A mixture of 2-chloro-4-iodo-5-methylpyridine (29 g, 114.412 mmol, 1.00equiv), acetimidamide hydrochloride (32.27 g, 343.236 mmol, 3 equiv),K₂CO₃(55.34 g, 400.442 mmol, 3.5 equiv) and CuI (43.58 g, 228.82 mmol, 2equiv) in DMF (70 mL) was stirred for overnight at 80° C. under nitrogenatmosphere. The mixture was allowed to cool down to r.t. The resultingmixture was diluted with EtOAc (1000 mL). The organic layers were washedwith sat. NaCl (aq.) (3×500 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to affordN-(2-chloro-5-methylpyridin-4-yl)acetimidamide (3 g, 14.28%) as a brownsolid. LC-MS: (ES+H, m/z): [M+H]⁺=184.0. ¹H NMR (400 MHz, DMSO-d₆) δ8.03 (s, 1H), 6.68 (s, 1H), 6.66-6.03 (m, 2H), 1.97 (s, 3H), 1.86 (s,3H).

Step 3: Preparation of methyl(E)-3-((1-((2-chloro-5-methylpyridin-4-yl)amino)ethylidene)amino)-3-oxopropanoate

To a stirred solution of N-(2-chloro-5-methylpyridin-4-yl)acetimidamide(700 mg, 3.812 mmol, 1.00 equiv) and 4-methylmorpholine (771.10 mg,7.624 mmol, 2 equiv) in DCM (10 mL) were added methyl3-chloro-3-oxopropanoate (1040.85 mg, 7.624 mmol, 2 equiv) dropwise at0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature. The reaction was quenched by the addition of sat.NaHCO₃ (aq.) (10 mL) at room temperature. The resulting mixture waspoured into water (50 mL). And the resulting mixture was extracted withEtOAc (3×50 mL). The combined organic layers were washed with sat. NaCl(aq.) (50 mL), then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to afford methyl(E)-3-((1-((2-chloro-5-methylpyridin-4-yl)amino)ethylidene)amino)-3-oxopropanoate(470 mg, 43.46%) as a brown solid. LC-MS: (ES+H, m/z): [M+H]⁺=283.8. ¹HNMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.14 (s, 1H), 6.85 (s, 1H), 3.63(s, 3H), 3.61 (s, 2H), 2.05 (s, 3H), 1.99 (s, 3H).

Step 4: Preparation of3-(2-chloro-5-methylpyridin-4-yl)-6-hydroxy-2-methylpyrimidin-4(3H)-one

To a stirred solution of methyl(E)-3-((1-((2-chloro-5-methylpyridin-4-yl)amino)ethylidene)amino)-3-oxopropanoate(2.8 g, 9.869 mmol, 1.00 equiv) in dioxane (20 mL) were added DBU (4.51g, 29.607 mmol, 3 equiv) dropwise at 0° C. under nitrogen atmosphere.The resulting mixture was stirred for 4 h at 80° C. under nitrogenatmosphere. The mixture was allowed to cool down to r.t. The resultingmixture was concentrated under vacuum. The residue was purified bysilica gel column chromatography to afford3-(2-chloro-5-methylpyridin-4-yl)-6-hydroxy-2-methylpyrimidin-4(3H)-one(2.1 g, 84.55%) as a brown solid. LC-MS: (ES+H, m/z): [M+H]⁺=252.0.

Step 5: Preparation of3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one

To a stirred mixture of3-(2-chloro-5-methylpyridin-4-yl)-6-hydroxy-2-methylpyrimidin-4-one(3.80 g, 15.10 mmol, 1.00 equiv) and2-(chloromethyl)-3,5-difluoropyridine (2.96 g, 18.12 mmol, 1.20 equiv)in DMF was added K₂CO₃ (6.26 g, 45.30 mmol, 3.00 equiv) and 18-Crown-6(399 mg, 1.51 mmol, 0.10 equiv) at room temperature under nitrogenatmosphere. The resulting mixture was stirred for 3 h at 60° C. undernitrogen atmosphere. The mixture was allowed to cool down to roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was purified by silica gel column chromatography to afford3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one(650 mg, 11.3%) as a yellow solid. LC-MS: (ES+H, m/z): [M+H]⁺=379.0.

Step 6: Preparation of5-chloro-3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one

To a stirred mixture of3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one(650 mg, 1.72 mmol, 1.00 equiv) and NCS (275 mg, 2.06 mmol, 1.20 equiv)in i-PrOH (2 ml) was added 2,2-dichloroacetic acid (22 mg, 0.17 mmol,0.10 equiv) dropwise at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at 60° C. under nitrogenatmosphere. The mixture was allowed to cool down to room temperature.The precipitated solids were collected by filtration and washed withi-PrOH (3×5 mL) to afford5-chloro-3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one(310 mg, 43.7%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=414.9.

Step 7: Preparation of4′-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one

To a stirred solution of5-chloro-3-(2-chloro-5-methylpyridin-4-yl)-6-[(3,5-difluoropyridin-2-yl)methoxy]-2-methylpyrimidin-4-one(297 mg, 0.72 mmol, 1.00 equiv) and3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (330 mg, 2.16 mmol, 3.00equiv) in 1,4-dioxane (10 ml) was added CuI (137 mg, 0.72 mmol, 1.00equiv), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (205 mg, 1.44mmol, 2.00 equiv), NaI (215 mg, 1.44 mmol, 2.00 equiv) and K₂CO₃(298 mg,2.16 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere.The resulting mixture was stirred for 24 h at 100° C. under nitrogenatmosphere. The resulting mixture was diluted with EtOAc (50 mL). Theresulting mixture was washed with 5% NH₃.H₂O (3×50 mL). The combinedorganic layer was washed with brine (50 mL), and then dried over Na₂SO₄.The solution was concentrated under reduced pressure. The residue waspurified by PREP-HPLC. This resulted in4′-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one(55 mg, 14.4%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=530.1.

Step 8: Preparation ofrel-4′-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one&rel-4′-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one

4′-{5-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2-methyl-6-oxopyrimidin-1-yl}-3-(2-hydroxypropan-2-yl)-5′-methyl-[1,2′-bipyridin]-2-one(55 mg) was separated by prep-chiral-HPLC to afford Example 25A (23.5mg, 99.1% purity, ee=100%) and Example 25B (19.6 mg, 98.7% purity,ee=98.7%) as a white solid.

Example 25A: LC-MS: (ES+H, m/z): [M+H]⁺=530.10. ¹H NMR (400 MHz,DMSO-d₆) δ 8.71 (s, 1H), 8.57 (d, 1H), 8.08-8.02 (m, 1H), 7.98 (s, 1H),7.85 (d, 1H), 7.70 (d, 1H), 6.43 (t, 1H), 5.63-5.59 (m, 2H), 5.22 (s,1H), 2.15 (s, 3H), 2.12 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). ¹⁹F NMR(400 MHz, DMSO-d₆) δ−120.38, −120.40, −123.00, −123.03.

Example 25B: LC-MS: (ES+H, m/z): [M+H]⁺=530.10. ¹H NMR (400 MHz,DMSO-d₆) δ 8.70 (s, 1H), 8.57 (d, 1H), 8.08-8.02 (m, 1H), 7.97 (s, 1H),7.85 (d, 1H), 7.70 (d, 1H), 6.43 (t, 1H), 5.63-5.59 (m, 2H), 5.21 (s,1H), 2.15 (s, 3H), 2.12 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). ¹⁹F NMR(400 MHz, DMSO-d₆) δ −120.38, −120.40, −123.01, −123.03.

Example 26A, 26B

Step 1: Preparation of ethyl 4-fluoro-2-methoxypyridine-3-carboxylate

To a stirred mixture of 4-fluoro-2-methoxypyridine-3-carboxylic acid(1.00 g, 5.84 mmol, 1.00 equiv) in DMF (20 mL) was added iodoethane(1.37 g, 8.76 mmol, 1.50 equiv) and K₂CO₃ (1.62 g, 11.68 mmol, 2.00equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 2 h at 50° C. under nitrogen atmosphere. Themixture was allowed to cool down to room temperature. The resultingmixture was diluted with EtOAc (100 mL). The resulting mixture waswashed with H₂O (5×60 mL) then brine (100 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure, to afford ethyl 4-fluoro-2-methoxypyridine-3-carboxylate (1.00g, crude) as a yellow solid. LC-MS: (ES+H, m/z): [M+H]⁺=200.3

Step 2: Preparation of ethyl 4-fluoro-2-oxo-1H-pyridine-3-carboxylate

To a stirred solution of ethyl 4-fluoro-2-methoxypyridine-3-carboxylate(900 mg, 4.51 mmol, 1.00 equiv) in MeCN (15 ml) was added TMSI (3.62 g,18.07 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere.The resulting mixture was stirred for 2 h at room temperature undernitrogen atmosphere. The resulting mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to afford ethyl 4-fluoro-2-oxo-1H-pyridine-3-carboxylate(800 mg, 95.6%) as a yellow solid. LC-MS: (ES+H, m/z): [M+H]⁺=186.3.

Step 3: Preparation of4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one

To a stirred solution of ethyl 4-fluoro-2-oxo-1H-pyridine-3-carboxylate(700 mg, 3.78 mmol, 1.00 equiv) in THF (70.00 mL) was added MeMgBr (3.7mL, 3M in 2-methyl-THF, 11.34 mmol, 3.00 equiv) dropwise at 0° C. undernitrogen atmosphere. The resulting mixture was stirred for 1 h at 0° C.under nitrogen atmosphere. The reaction was quenched by the addition ofsat. NH₄Cl (aq.) (20 mL) at 0° C. The resulting mixture was extractedwith EtOAc (3×100 mL). After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by reverse flashchromatography. This resulted in4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (400 mg, 61.8%) as awhite solid. LC-MS: (ES+H, m/z): [M+H]⁺=172.3.

Step 4: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2′-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred mixture of2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(500 mg, 1.09 mmol, 1.00 equiv) and4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyridin-2-one (373 mg, 2.180 mmol,2.00 equiv) in dioxane (10 mL) was added CuI (41 mg, 0.21 mmol, 0.20equiv), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (62 mg, 0.43mmol, 0.40 equiv) and K₂CO₃ (301 mg, 2.18 mmol, 2.00 equiv) at roomtemperature under nitrogen atmosphere. The resulting mixture was stirredfor 3 h at room temperature under nitrogen atmosphere. The resultingmixture was diluted with EtOAc (50 mL). The combined organic layers werewashed with brine (2×100 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by PREP-HPLC to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2′-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(280 mg, 46.7%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=549.2.

Step 5: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2′-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one&rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2′-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

3-chloro-4-[(3,5-difluoropyridin-2-yl)(2H2)methoxy]-2′-[4-fluoro-3-(2-hydroxypropan-2-yl)-2-oxopyridin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(200 mg) was separated by prep-chiral-HPLC to afford Example 26A (80.6mg, 99.4% purity, 97.3% deuterium purity, ee=100%) and Example 26B (82.5mg, 97.7% purity, 97.1% deuterium purity, ee=99%) as a white solid.

Example 26A: LC-MS: (ES+H, m/z): [M+H]⁺=549.05. ¹H NMR (300 MHz,DMSO-d₆) δ 8.71 (s, 1H), 8.61 (d, 1H), 8.17-8.03 (m, 2H), 7.81 (s, 1H),6.81 (d, 1H), 6.56-6.53 (m, 1H), 6.41 (s, 1H), 2.09 (s, 3H), 2.03 (s,3H), 1.52 (s, 3H), 1.50 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−91.28,−120.25, −120.27, −122.32, −122.35.

Example 26B: LC-MS: (ES+H, m/z): [M+H]⁺=549.1. ¹H NMR (300 MHz, DMSO-d₆)δ 8.71 (s, 1H), 8.61 (d, 1H), 8.17-8.03 (m, 2H), 7.81 (s, 1H), 6.81 (d,1H), 6.56-6.53 (m, 1H), 6.41 (s, 1H), 2.09 (s, 3H), 2.03 (s, 3H), 1.51(s, 3H), 1.50 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−91.28, −120.25,−120.27, −122.32, −122.35.

Example 27A, 27B

Step 1&2: Preparation of Methyl2-{[(2,2-dimethoxyethyl)carbamoyl]amino}-2-methylpropanoate

To a stirred mixture of 3-methoxy-2,2-dimethyl-3-oxopropanoic acid (2.00g, 13.68 mmol, 1.00 equiv) and Et₃N (1.52 g, 15.05 mmol, 1.10 equiv) inDME (20 mL) was added DPPA (4.14 g, 15.05 mmol, 1.10 equiv) dropwise at0° C. under nitrogen atmosphere. The resulting mixture was stirred for30 min at room temperature under nitrogen atmosphere. The resultingmixture was stirred for additional 2 h at 90° C. under nitrogenatmosphere. To the above mixture was added 2,2-dimethoxyethanamine (2.88g, 27.37 mmol, 2.00 equiv) at room temperature. The resulting mixturewas stirred for additional 2 h at room temperature. The reaction wasquenched by the addition of sat. NaHCO₃ (aq.) (20 mL) at roomtemperature. The resulting mixture was extracted with EtOAc (3×30 mL).The combined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure to afford methyl2-{[(2,2-dimethoxyethyl)carbamoyl]amino}-2-methylpropanoate (2.20 g,crude) as a colorless liquid. LC-MS: (ES+H, m/z): [M+H]⁺=249.1.

Step 3: Preparation of methyl2-methyl-2-(2-oxo-3H-imidazol-1-yl)propanoate

To a stirred mixture of methyl2-{1[(2,2-dimethoxyethyl)carbamoyl]amino}-2-methylpropanoate (2.20 g,8.86 mmol, 1.00 equiv) in THF (5 mL) was added TFA (2.5 mL) dropwise atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred for 1 h at 70° C. under nitrogen atmosphere. The residue waspurified by reverse flash chromatography to afford methyl2-methyl-2-(2-oxo-3H-imidazol-1-yl)propanoate (1.00 g, 39.67%) as awhite solid. LC-MS: (ES+H, m/z): [M+H]⁺=185.1. ¹H NMR (300 MHz, DMSO-d₆)δ 9.96 (s, 1H), 6.54 (dd, 1H), 6.35 (t, 1H), 3.59 (s, 3H), 1.52 (s, 6H).

Step 4: Preparation of1-(1-hydroxy-2-methylpropan-2-yl)-3H-imidazol-2-one

To a stirred mixture of methyl2-methyl-2-(2-oxo-3H-imidazol-1-yl)propanoate (600 mg, 3.25 mmol, 1.00equiv) in THF (6 mL) was added LiAlH₄ (247 mg, 6.51 mmol, 2.00 equiv) inportions at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for 30 min at room temperature under nitrogen atmosphere. Thereaction was quenched with water at 0° C. The resulting mixture wasextracted with EtOAc (3×10 mL). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure to afford1-(1-hydroxy-2-methylpropan-2-yl)-3H-imidazol-2-one (360 mg, crude) as awhite solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.97 (s, 1H), 6.50 (dd, 1H),6.35 (t, 1H), 5.28 (t, 1H), 3.68 (d, 2H), 1.42 (s, 6H).

Step 5: Preparation of3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxoimidazol-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(500 mg, 1.09 mmol, 1.00 equiv),1-(1-hydroxy-2-methylpropan-2-yl)-3H-imidazol-2-one (342 mg, 2.19 mmol,2.00 equiv), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (62 mg, 0.43mmol, 0.40 equiv), K₂CO₃ (302 mg, 2.19 mmol, 2.00 equiv) and CuI (41 mg,0.21 mmol, 0.20 equiv) in dioxane (5 ml) was stirred for 2 h at 80° C.under nitrogen atmosphere. The mixture was allowed to cool down to roomtemperature. The resulting mixture was diluted with EtOAc (20 mL). Theresulting mixture was washed with water (10% NH₃.H₂O, 3×20 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The crude product was purified by Prep-HPLC to afford3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxoimidazol-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(305 mg, 52.37%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=532.25.

Step 6: Preparation ofrel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxoimidazol-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one&rel-3-chloro-4-[(3,5-difluoropyridin-2-yl)methoxy]-2′-[3-(1-hydroxy-2-methylpropan-2-yl)-2-oxoimidazol-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The racemate (300 mg) was separated by prep-SFC to afford Example 27A(91.3 mg, 98.1% purity, ee=100.0%) as a white solid and Example 27B(82.9 mg, 99.7% purity, ee=99.5%) as a white solid.

Example 27A: LC-MS: (ES+H, m/z): [M+H]⁺=532.2. ¹H NMR (400 MHz, DMSO-d₆)δ 8.60 (d, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 8.14-8.01 (m, 1H), 7.30 (d,1H), 6.80 (s, 1H), 6.79 (d, 1H), 5.49 (d, 2H), 4.99 (t, 1H), 3.77-3.61(m, 2H), 1.99 (s, 3H), 1.98 (s, 3H), 1.43 (s, 6H). ¹⁹F NMR (377 MHz,DMSO-d₆) δ −120.20, −120.22, −122.42, −122.44.

Example 27B: LC-MS: (ES+H, m/z): [M+H]⁺=532.1. ¹H NMR (400 MHz, DMSO-d₆)δ 8.60 (d, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 8.14-8.05 (m, 1H), 7.30 (d,1H), 6.80 (s, 1H), 6.79 (d, 1H), 5.49 (d, 2H), 4.99 (t, 1H), 3.79-3.57(m, 2H), 1.99 (s, 3H), 1.99 (s, 3H), 1.43 (s, 6H). ¹⁹F NMR (377 MHz,DMSO-d₆) δ −120.20, −120.22, −122.42, −122.44.

Example 28A, 28B

Step 1: Preparation of Ethyl 3-fluoro-5-methylpyridine-2-carboxylate

To a stirred mixture of 2-bromo-3-fluoro-5-methylpyridine (4.00 g, 21.05mmol, 1.00 equiv) and Pd(dppf)C₁₂ (1.54 g, 2.10 mmol, 0.10 equiv) inEtOH (40 mL) were added Et₃N (25.56 g, 252.61 mmol, 3.00 equiv) dropwiseat room temperature. The resulting mixture was stirred for 18 h at 80°C. under carbon monoxide atmosphere (50 atm). The mixture was allowed toroom temperature. The resulting mixture was concentrated under reducedpressure. The resulting mixture was diluted with CH₂Cl₂ (200 mL), washedwith 3×100 mL of H₂O. The organic layers were concentrated under reducedpressure and purified by silica gel column chromatography to affordethyl 3-fluoro-5-methylpyridine-2-carboxylate (3.10 g, 80.39%) as awhite solid. LC-MS: (ES+H, m/z): [M+H]⁺=184.1. ¹H NMR (300 MHz, DMSO-d₆)δ 8.35 (d, 1H), 7.71-7.68 (m, 1H), 4.37-4.30 (m, 2H), 2.37 (s, 3H), 1.30(t, 3H).

Step 2: Preparation of (3-fluoro-5-methylpyridin-2-yl)(2H2)methanol

To a stirred mixture of ethyl 3-fluoro-5-methylpyridine-2-carboxylate(3.00 g, 16.37 mmol, 1.00 equiv) in solution of CD₃OD (10 mL) and THF(20 mL) were added Sodium borodeuteride (1.86 g, 49.13 mmol, 3.00 equiv)in portions at 0° C. under nitrogen atmosphere. The resulting mixturewas stirred for 2 h at room temperature under nitrogen atmosphere. Thefiltrate was quenched by the addition of D₂O (4 mL) at 0° C. Theresulting mixture was diluted with ethyl acetate (300 mL), washed with3×100 mL of H₂O. The organic layers were dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.To afford (3-fluoro-5-methylpyridin-2-yl)(2H2)methanol (2.4 g, crude) asa yellow liquid. LC-MS: (ES+H, m/z): [M+H]⁺=144.3. ¹H NMR (300 MHz,DMSO-d₆) δ 8.23 (d, 1H), 7.55-7.50 (m, 1H), 5.20 (s, 1H), 2.32 (s, 3H).

Step 3: Preparation of 2-[chloro(2H2)methyl]-3-fluoro-5-methylpyridine

To a stirred mixture of (3-fluoro-5-methylpyridin-2-yl)(2H2)methanol(2.40 g, 16.76 mmol, 1.00 equiv) and DMF (0.1 mL, 1.67 mmol, 0.10 equiv)in DCM (24 mL) were added SOCl₂ (2.6 mL, 36.88 mmol, 2.20 equiv)dropwise at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for 2 h at room temperature under nitrogen atmosphere. Theresulting mixture was concentrated under vacuum to afford2-[chloro(2H2)methyl]-3-fluoro-5-methylpyridine (3.30 g, crude) as abrown yellow liquid. LC-MS: (ES+H, m/z): [M+H]⁺=162.1. ¹H NMR (300 MHz,DMSO-d₆) δ 8.29 (d, 1H), 7.69-7.64 (m, 1H), 2.35 (s, 3H).

Step 4: Preparation of2′-bromo-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of 2′-bromo-4-hydroxy-5′,6-dimethyl-[1,4′-bipyridin]-2-one(2.57 g, 8.72 mmol, 1.00 equiv),2-[chloro(2H2)methyl]-3-fluoro-5-methylpyridine (3.10 g, 19.18 mmol,2.20 equiv), 18-Crown-6 (691 mg, 2.61 mmol, 0.30 equiv) and K₂CO₃ (7.23g, 52.31 mmol, 6.00 equiv) in DMF (25 mL) was stirred for 2 h at 60° C.under nitrogen atmosphere. The mixture was allowed to room temperature.The resulting mixture was diluted with ethyl acetate (200 mL). Theresulting mixture was washed with brine (3×100 mL). The organic layerdried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to afford2′-bromo-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(2.30 g, 62.76%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=420.1. ¹HNMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.34 (d, 1H), 7.73 (s, 1H),7.70-7.67 (m, 1H), 6.12 (d, 1H), 6.02 (d, 1H), 2.37 (s, 3H), 1.96 (s,3H), 1.85 (s, 3H).

Step 5: Preparation of2′-bromo-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

To a stirred solution of2′-bromo-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(600 mg, 1.42 mmol, 1.00 equiv) and NCS (190 mg, 1.42 mmol, 1.00 equiv)in IPA (6 mL) was added 2,2-dichloroacetic acid (18 mg, 0.14 mmol, 0.10equiv) at room temperature under air atmosphere. The resulting mixturewas stirred for 1 h at 60° C. under nitrogen atmosphere. The mixture wasallowed to cool down to 4° C. The precipitated solids were collected byfiltration and washed with cold IPA (3×40 mL). To afford2′-bromo-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(380 mg, 58.54%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=455.90. ¹HNMR (300 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.36 (d, 1H), 7.82 (s, 1H),7.73-7.69 (m, 1H), 6.82 (s, 1H), 2.38 (s, 3H), 1.96 (s, 6H).

Step 6: Preparation of3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

A mixture of2′-bromo-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(380 mg, 0.83 mmol, 1.00 equiv),3-(2-hydroxypropan-2-yl)-1H-pyrazin-2-one (386 mg, 2.50 mmol, 3.00equiv), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (47 mg, 0.33 mmol,0.40 equiv), CuI (31 mg, 0.16 mmol, 0.20 equiv) and K₂CO₃ (230 mg, 1.67mmol, 2.00 equiv) in 1,4-dioxane (3 mL) was stirred for 2 h at 80° C.under nitrogen atmosphere. The mixture was allowed to room temperature.The resulting mixture was diluted with ethyl acetate (100 mL) and washedwith water (10% NH₃, 3×50 mL). The organic layer was concentrated underreduced pressure to afford crude product, which was further purified byPREP-HPLC. This resulted in3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one(107 mg, 24.25%) as a white solid. LC-MS: (ES+H, m/z): [M+H]⁺=528.20. ¹HNMR (300 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.36 (d, 1H), 8.00 (d, 1H), 7.95(s, 1H), 7.73-7.69 (m, 1H), 7.47 (d, 1H), 6.83 (s, 1H), 5.12 (s, 1H),2.39 (s, 3H), 2.10 (s, 3H), 2.01 (s, 3H), 1.51 (s, 6H).

Step 7: Preparation ofrel-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-oneandrel-3-chloro-4-[(3-fluoro-5-methylpyridin-2-yl)(2H2)methoxy]-2′-[3-(2-hydroxypropan-2-yl)-2-oxopyrazin-1-yl]-5′,6-dimethyl-[1,4′-bipyridin]-2-one

The racemate (102 mg) was separated by Prep-Chiral-HPLC to affordExample 28A (35.4 mg, 99.6% purity, ee=100%) as a white solid andExample 28B (26.7 mg, 99.7% purity, ee=100%) as a white solid.

Example 28A: LC-MS: (ES+H, m/z): [M+H]⁺=528.20. ¹H NMR (300 MHz,DMSO-d₆) δ 8.75 (s, 1H), 8.36 (d, 1H), 8.00 (d, 1H), 7.95 (s, 1H),7.73-7.69 (m, 1H), 7.47 (d, 1H), 6.83 (s, 1H), 5.13 (s, 1H), 2.38 (s,3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−126.30.

Example 28B: LC-MS: (ES+H, m/z): [M+H]⁺=528.20. ¹H NMR (300 MHz,DMSO-d₆) δ 8.75 (s, 1H), 8.36 (d, 1H), 8.00 (d, 1H), 7.95 (s, 1H),7.73-7.69 (m, 1H), 7.47 (d, 1H), 6.83 (s, 1H), 5.13 (s, 1H), 2.38 (s,3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.51 (s, 6H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−126.30.

BIOLOGICAL EXAMPLES Protein Expression and Purification

Expression vectors of the recombinant MK2 and PRAK kinases wereconstructed by cloning of the codon optimized gene sequences of MK2(Uniprot ID P49137, amino acid fragment F46-H400), or PRAK (Uniprot IDQ81W41, amino acid fragment M1-Q471) into pGEX-4T1 (GE) for overexpression of these kinases with N-terminal GST-tag. Protein expressionwas carried out in E. coli BL21 by growing the hosts in TB medium,induction of protein expression with 0.5 mM IPTG at approximate 0.8OD₆₀₀, and incubation of the cultures at 18° C. for 14-20 hoursafterwards. The harvested cells were resuspended in 100 ml of Lysisbuffer (50 mM Tris-HCl, pH 8.0, 500 mM NaCl, 1 mM DTT, 5% glycerol, and1 mM PMSF) per gram of wet cell mass and homogenized at 4° C. in amicrofluidizer (ATS, Suzhou, China) at 14,000 psi pressure, 3 passes.The cell lysates were clarified by centrifugation and the supernatantscontaining the GST-fusion proteins were purified by affinitychromatography using GSH-Sepharose (GE) gravity flow columnspre-equilibrated in Buffer A (50 mM Tris-HCl, pH 8.0, 500 mM NaCl, 1 mMDTT, and 5% glycerol). After thorough washing of the columns with BufferA, the bound GST-proteins were eluted by Buffer B (50 mM Tris, pH 8.0,500 mM NaCl, 1 mM DTT, 5% glycerol, 10 mM glutathione), followed bysize-exclusion purification on Superdex 200 column equilibrated inBuffer A. The purified proteins were concentrated to approximately 1mg/ml and stored at −80° C.

Biochemical Assay

This study evaluates the inhibitory potency of invention compound onp38/MK2 pathway vs p38/PRAK pathway. More specially the compoundconcentration (IC₅₀) was determined that inhibited half of the maximalactivation of MK2 or PRAK by p38. MK2 activation study was set upwithout or with a serial of 10-point 1:3 dilution of invention compoundat top dose of 1 or 10 μM, and PRAK activation study was set up withoutor with a serial of 10-point 1:3 dilution of invention compound at topdose of 300 μM. The MIK2 and PRAK activity were determined by thephosphorylation level of HSP27 peptide conjugated with FITC.

A typical assay was conducted in 20 μL volume including 60 μM activep38α (Carna, cat #04-152), 10 μM ATP, 1 μM FITC-HSP27 peptide (Sangon,Cat #P22354), and 1 nM inactive MK2, or PRAK in 1× reaction buffer (20mM HEPES, pH7.5, 10 mM MgCl₂, 1 mM DTT, 0.0100 Triton X-100, 0.01% BSA).After 2 h incubation of the reaction mixture with various concentrationof invention compound (200 nL), 60 μL 1×IMAP solution Mixture (MolecularDevices, Cat #R8127) was added to the reaction mixture and incubated foranother half hour. The signal was then read by Synergy™ Neo2 Multi-ModeMicroplate Reader with filter setting (Ex/Em=485 nm/FITC FP-P pol 528 nm& FITC FP-S pol 528 nm)

The signal was then normalized to vehicle control and fitted in Xfit togenerate IC₅₀. The selectivity of MK2 over PRAK was calculated by theformular Selectivity=IC₅₀ of PRAK/IC₅₀ of MK2.

The data from the above assays is found in table 2.

TABLE 2 p38a/MK2 (10 μM) p38a/MK2 p38a/PRAK Ex. Enzyme pIC₅₀ (1 μM)Enzyme pIC₅₀ Enzyme pIC₅₀  1A 8.5 8.7 5.5  1B 6.4 <3.5  2A 8.4 5.9  2B<6.0 <3.5  3A 8.2 5.3  3B <6.0 <3.5  4A 8.7 5.3  4B <6.0 <3.5  5A 8.65.6  5B <6.0 <3.5  6 7.7 5.2  7A 9 5.1  7B <6.0 <3.5  8A 9.1 5.6  8B<6.0 <3.5  9A 7.9 5.7  9B <6.0 <3.5 10A 7 5.4 10B <6.0 <3.5 11A 8.4 5.311B <6.0 <3.5 12A 7.9 5.1 12B <6.0 <3.5 13A <6.0 <3.5 13B <6.0 4.8 14A8.8 5.5 14B 8.9 5.5 14C <6.0 <3.5 14D <6.0 <3.5 15A 8 5.6 15B <6.0 <3.516A 6.7 5.1 16B <6.0 <3.5 17A 8.8 5.2 17B <6.0 <3.5 18A 8.8 5.5 18B <7.0<3.5 19A 9 5.8 19B 6.1 <3.5 20A 9 5.5 20B 6.5 <3.5 21A 8.9 5.3 21B <6.0<3.5 22A 8.7 5.4 22B <7.0 <3.5 23A 8.6 5.2 23B <7.0 <3.5 24A <6.0 <3.524B 8.6 5.3 25A 8.4 5.2 25B 6.2 <3.5 26A 8.6 5.5 26B <7.0 <3.5 27A <7.0<3.5 27B 7.9 6.1 28A 9.0 5.5 28B <7.0 <3.5

1. A compound of Formula (I), or a pharmaceutically acceptable salt,solvate, stereoisomer, or rotamer thereof:

wherein: Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R¹⁰ is independently hydrogen, deuterium, halogen, —CN, —NO₂, —OH,—OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),—NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isoptionally and independently substituted with one or more R^(10a); ortwo R¹⁰ on the same atom are taken together to form an oxo; each R^(10a)is independently deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),—OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),—NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R^(10a) on thesame atom are taken together to form an oxo; n is 1-4; R¹ and R² areindependently hydrogen, deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, orheterocycloalkyl; or R¹ and R² are taken together to form an oxo; or R¹and R² are taken together to form a cycloalkyl or heterocycloalkyl;wherein the cycloalkyl and heterocycloalkyl is optionally substitutedwith deuterium, halogen, —CN, —OH, —OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂,—C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, orC₁-C₆heteroalkyl; X is —C(R³)₂—, —NR⁴—, —O—, or —S—; each R³ areindependently hydrogen, deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, orheterocycloalkyl; or two R³ are taken together to form an oxo; R⁴ ishydrogen, —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, orheterocycloalkyl; R⁵ is hydrogen, deuterium, halogen, —CN, —NO₂, —OH,—OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, or heterocycloalkyl; R⁶ is hydrogen, deuterium, halogen,—CN, —NO₂, —OH, —OR^(a), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, or heterocycloalkyl; R⁷ is hydrogen,deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl;Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R¹¹ isindependently hydrogen, deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),—OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),—NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isoptionally and independently substituted with one or more R^(11a); ortwo R¹¹ on the same atom are taken together to form an oxo; each R^(11a)is independently deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),—OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),—NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R^(11a) on thesame atom are taken together to form an oxo; m is 1-4; Ring C isN-linked pyridinone, N-linked pyrimidinone, N-linked pyrazinone, orN-linked pyridazinone; each R¹² is independently hydrogen, deuterium,halogen, —CN, —NO₂, —OH, —OR^(a), —OC(═O)R^(a), —OC(═O)OR^(b),—OC(═O)NR^(c)R^(d), —SH, —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(c)R^(d), —S(═O)(═NR^(b))R^(a), —SiR^(c)R^(d)OR^(b),—NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),—NR^(b)C(═O)OR^(b), —NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein the alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isoptionally and independently substituted with one or more R^(12a); eachR^(12a) is independently deuterium, halogen, —CN, —NO₂, —OH, —OR^(a),—OC(═O)R^(a), —OC(═O)OR^(b), —OC(═O)NR^(c)R^(d), —SH, —SR^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —NR^(c)R^(d),—NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),—NR^(b)S(═O)₂R^(a), —C(═O)R^(a), —C(═O)C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), —C(═O)C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; or two R^(12a) on the same atom are taken together to forman oxo; p is 1-4; each R^(a) is independently C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylene(cycloalkyl),C₁-C₆alkylene(heterocycloalkyl), C₁-C₆alkylene(aryl), orC₁-C₆alkylene(heteroaryl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —S(═O)₂NHCH₃,—S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃, —C(═O)OH, —C(═O)OCH₃,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; each R^(b) is independentlyhydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃,—C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; and each R^(c)and R^(d) are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylene(cycloalkyl), C₁-C₆alkylene(heterocycloalkyl),C₁-C₆alkylene(aryl), or C₁-C₆alkylene(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃,—C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; or R^(c) andR^(d) are taken together with the atom to which they are attached toform a heterocyclo alkyl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃,—C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; or R^(b) andR^(c) are taken together with the atom to which they are attached toform a heterocycloalkyl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃,—C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; or R^(a) andR^(b) are taken together with the atom to which they are attached toform a heterocycloalkyl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃,—C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl; or two R^(b)are taken together with the atom to which they are attached to form aheterocycloalkyl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—S(═O)₂NHCH₃, —S(═O)₂N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(═O)CH₃,—C(═O)OH, —C(═O)OCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, or C₁-C₆heteroalkyl.
 2. The compoundof claim 1, or a pharmaceutically acceptable salt, solvate,stereoisomer, or rotamer thereof, wherein the compound of Formula (I) isa compound of Formula (Ia):


3. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, stereoisomer, or rotamer thereof, wherein the compound ofFormula (I) is a compound of Formula (Ib):


4. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, stereoisomer, or rotamer thereof, wherein the compound ofFormula (I) is a compound of Formula (Ic):


5. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, stereoisomer, or rotamer thereof, wherein the compound ofFormula (I) is a compound of Formula (Id):


6. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, stereoisomer, or rotamer thereof, wherein the compound ofFormula (I) is a compound of Formula (Ie):


7. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, stereoisomer, or rotamer thereof, wherein Ring A is pyridyl. 8.The compound of claim 1, or a pharmaceutically acceptable salt, solvate,stereoisomer, or rotamer thereof, wherein each R¹⁰ is independentlyhydrogen or halogen.
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or rotamer thereof, wherein n is1 or
 2. 10. The compound of claim 1, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or rotamer thereof, wherein R¹ and R² arehydrogen or deuterium.
 11. The compound of claim 1, or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof, wherein X is —O—.
 12. The compound of claim 1, or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof, wherein R⁵ is hydrogen, deuterium, halogen, —CN, or C₁-C₆alkyl.13. The compound of claim 1, or a pharmaceutically acceptable salt,solvate, stereoisomer, or rotamer thereof, wherein R⁶ is hydrogen,deuterium, halogen, —CN, or C₁-C₆alkyl.
 14. The compound of claim 1, ora pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof, wherein R⁷ is hydrogen, deuterium, or halogen.
 15. The compoundof claim 1, or a pharmaceutically acceptable salt, solvate,stereoisomer, or rotamer thereof, wherein Ring B is a phenyl or a6-membered heteroaryl.
 16. The compound of claim 1, or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof, wherein each R¹¹ is independently hydrogen or C₁-C₆alkyl. 17.The compound of claim 1, or a pharmaceutically acceptable salt, solvate,stereoisomer, or rotamer thereof, wherein m is 1 or
 2. 18. The compoundof claim 1, or a pharmaceutically acceptable salt, solvate,stereoisomer, or rotamer thereof, wherein each R¹² is independentlyhydrogen, deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, cycloalkyl, heterocycloalkyl,C₁-C₆alkylene(cycloalkyl), or C₁-C₆alkylene(heterocycloalkyl); whereinthe alkyl, cycloalkyl, and heterocycloalkyl is optionally andindependently substituted with one or more R^(12a).
 19. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer,or rotamer thereof, wherein each R¹² is independently hydrogen,deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl,cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, andheterocycloalkyl is optionally and independently substituted with one ormore R^(12a).
 20. The compound claim 1, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or rotamer thereof, wherein p is 1 or 2.21. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.
 22. The compound of claim 1 that is:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.
 23. The compound of claim 1 that is:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.
 24. The compound of claim 1 that is:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.
 25. The compound of claim 1 that is:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.
 26. The compound of claim 1 that is:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.
 27. The compound of claim 1 that is:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.
 28. The compound of claim 1 that is:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof.
 29. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or rotamer thereof, and apharmaceutically acceptable excipient.
 30. A method for treating acondition comprising administering to a subject in need thereof atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, solvate, stereoisomer, or rotamerthereof, wherein the condition is selected from the group consisting ofan autoimmune disorder, a chronic inflammatory disorder, an acuteinflammatory disorder, an auto-inflammatory disorder, a fibroticdisorder, a metabolic disorder, a neoplastic disorder, and acardiovascular or a cerebrovascular disorder.